Introduction
Acute HIV infection is often accompanied by a flu-like illness and is associated with a high-titer viremia. This viremia is quickly controlled by the immune response, mediated predominantly by cytotoxic CD8+ T lymphocytes (CTL), and, to some extent, by anti-HIV antibodies.1,2 In most individuals, plasma viral load is maintained at low levels for years and the individual remains asymptomatic. However, during this ‘clinical latency’, plasma viral RNA is detectable and viral turnover is brisk, with large numbers of viruses produced and destroyed each day.3 For reasons that are not yet clear, a break in this control leads to a significant decline in the number of CD4+ T cells, and a rapid increase in viral load. It is after this break in immune control that the clinical symptoms of AIDS appear.4
Over the past several years, tremendous progress has been made in our understanding of the biology of HIV infection and the mechanisms of HIV replication and its control. However, the biochemical mechanism(s) of HIV-induced T cell death, including death of uninfected CD4+ and CD8+ T cells, are not well defined. Here, we discuss the role of viral and cellular proteins in HIV-infected and -uninfected T cell death. We also discuss mechanisms by which HIV may actually protect infected T cells from apoptosis. Current therapy to enhance immune system function and to decrease bystander T cell death (thereby, increasing CD4+ T cell number) in HIV infected individuals will also be discussed.
Apoptosis of HIV infected T cells
In HIV infected individuals, viral load is a good predictor of disease progression: the higher the viral load, the faster the disease progression.5,6 Some studies have also shown a correlation between the extent of apoptosis and disease progression,7,8 suggesting that, in vivo, HIV kills the CD4+ T cell that it infects. These observations argue that the virus is responsible for the depletion of CD4+ T cells. Not addressed by these studies, however, are the mechanisms by which HIV depletes its host of CD4+ T cells. In this section of the review, we will focus on mechanisms of T cell killing by HIV, although recent data suggest that failure of T cell regeneration also plays an important role in CD4+ T cell loss in HIV disease.9,10 In later sections of this review, we will discuss an alternate thesis, based on data suggesting that HIV and SIV have evolved mechanisms of blocking or delaying the cellular suicide program. Tables 1,2 and 3 summarize much of the published data on cell death in HIV disease. Interestingly, several HIV gene products have been reported to both induce and inhibit apoptosis, a recurring theme in the apoptosis literature.
One major pathway of T cell apoptosis is mediated through the tumor necrosis factor (TNF) family of receptors. The Fas receptor, in particular, has been extensively studied in recent years. Ligation of Fas by Fas ligand (FasL), present on the same or on a neighboring cell, can induce apoptosis.11,12,13 Data are controversial regarding involvement of Fas in HIV-induced T cell death (reviewed in14,15).
Peripheral blood lymphocytes (PBL) from HIV+ individuals have higher Fas expression,16 and the proportion of Fas-expressing T cells increases with disease progression.17 CD4+ and CD8+ T cells from HIV infected individuals are more susceptible to death induced by Fas ligation.16,18 In vitro studies from our lab show that HIV infected T cells become more susceptible to Fas induced apoptosis.19 In this study, we showed that the increase in sensitivity of HIV infected cells to Fas killing mapped to the HIV gene product, Vpu. Another viral protein, Tat, has been shown to sensitize T cells to TCR- and CD4-induced apoptosis by upregulation of FasL expression,20 and to increase the sensitivity to Fas mediated apoptosis by upregulation of caspase-8.21 Furthermore, Nef has been shown to increase surface expression of both Fas and FasL, and Nef's ability to interact with cellular kinases is required for this increased expression and for apoptosis.22
Viruses are notorious for interfering in ‘internal matters’ of the host cell in ways which may be beneficial to the virus, but which may ultimately induce cell death. Tat, one of the early HIV gene products, has been shown to induce reactive oxygen intermediates, caspase activation, and activation of NF-κB, AP-1, and JNK, in a p56lck dependent manner.23 These data suggest that binding of HIV to CD4 activates p56lck and other downstream signaling events, which prepares the cell for HIV production (for example, by NF-κB activation), but which also induces apoptosis (for example, by caspase activation).
One of the accessory proteins of HIV-1, Vpr, has been shown to induce T cell apoptosis. Synthetic Vpr added to intact T cells causes a rapid dissipation of the mitochondrial transmembrane potential, as well as the release of cytochrome c and cellular apoptosis.24 These data support evidence of Macho et al. showing that T cells from HIV+ individuals have dysfunctional mitochondria, reduced mitochondrial transmembrane potential, and increased generation of superoxide anion.25 The dissipation of the mitochondrial transmembrane potential and the apoptosis induced by Vpr can be inhibited by the cellular anti-apoptotic protein, Bcl-2.24 But HIV has also been shown to down-regulate Bcl-2 by a number of different mechanisms. Levels of Bcl-2 are significantly lower in PBL from HIV infected individuals with high levels of viral replication.26 Spontaneous apoptosis of CD4+ and CD8+ T cells from HIV infected individuals correlates with downregulation of Bcl-2 and is partially prevented by anti-retroviral therapy or by IL-2.27 The HIV-1 transcriptional regulatory protein, Tat, has been shown to decrease Bcl-2 expression.28 HIV protease has been shown to cleave Bcl-2 and this is correlated with induction of apoptosis.29,30 Another mechanism of HIV induced downregulation of Bcl-2 may be via inhibition of the JAK3 (Janus Family kinase)/STAT5 (Signal Transducers and Activators of Transcription) activation pathway, which is necessary for growth factor-dependent T cell proliferation and survival.31 Interestingly, our data show that the HIV-1 clonal isolate, NL4-3, inhibits the JAK3/STAT5 activation pathway (Selliah and Finkel, manuscript submitted). The JAK3/STAT5 signaling pathway has been shown to upregulate anti-apoptotic proteins, such as Bcl-2 and Bcl-xL.31,32 These data suggest that HIV mediated inhibition of anti-apoptotic mechanisms in host cells may further enhance spontaneous apoptosis or the apoptosis induced by Vpr or other viral proteins.
Another function of Vpr is cell cycle arrest. Relevant to our subsequent discussion of HIV-induced death of bystander cells, Vpr induces cell cycle arrest in both infected and uninfected cells.33 Vpr arrests cells in the G2 phase of the cell cycle by inhibiting activation of p34cdc2-cyclin B.34,35 The activity of p34cdc2-cyclin B is critical for entry into mitosis and requires removal of the phosphate residues on p34cdc2 that inhibit kinase function.35 In Vpr expressing cells, phosphatase cdc25C, which removes phosphate from p34cdc2, is in an inactive form, suggesting that the target for Vpr is either cdc25C or an upstream regulator of cdc25C. Recently, Hrimech et al. reported that Vpr mediates G2 arrest by forming a complex with protein phosphatase 2A (PP2A), an upstream regulator of cdc25, and enhances the nuclear import of PP2A.36 In the nucleus, Vpr-PP2A complex binds and dephosphorylates cdc25, rendering it inactive.
G2 arrest by Vpr has been characterized as beneficial to HIV, resulting in production of more virions, although the cellular response to this arrest is suicide.34,35 Interestingly, Nishizawa et al. reported recently that a carboxy-terminal truncation of Vpr induces apoptosis via G1 arrest of the cell cycle.37 Another study showed that apoptosis induced by Vpr requires caspase activation.38 These data show that Vpr may regulate cellular function, including the cell cycle, and induce apoptosis via multiple and complex pathways. Our recent data suggest that another HIV-1 accessory protein, Vif, contributes to the aberrant cell cycle regulation and apoptosis in HIV infected T cells (Casella et al., manuscript submitted). Collectively, these data argue that HIV interferes with cellular functions for the benefit of replication and production of more virus, but that the cellular response to this interference is activation of apoptotic signaling pathways (Figure 1).
Apoptosis of uninfected T cells: bystander cell death
Despite the high viral burden and turnover throughout the course of HIV infection, only a small fraction (<0.1%) of CD4+ T cells are productively infected.39 Notably, the number of apoptotic CD4+ T cells from the peripheral blood of HIV-infected individuals is greater than the number of infected cells, suggesting that uninfected cells die by apoptosis.40 Apoptosis is seen in PBL of HIV infected individuals in both the CD4+ and CD8+ T cell subsets.7,8,40,41 A study of a large cohort of HIV-infected individuals at various stages of disease showed that the degree of apoptosis was significantly higher in CD4+, CD8+, and B cells, compared to uninfected individuals, and was correlated with disease progression.7 This study showed a low level of apoptosis in long-term non-progressors and a high level of apoptosis in rapid progressors. In the lymph nodes, the major site of viral replication,4,39 we have shown that apoptosis is increased in the lymph nodes of HIV-infected children, adults and SIV-infected macaques, when compared to lymph nodes from uninfected controls.42,43 Intriguingly, productively infected cells were only rarely apoptotic and apoptotic cells were only rarely productively infected.43 These data have been corroborated by Haase and coworkers in subsequent in situ analyses of apoptosis and infection44 (and personal communication). In addition, numbers of apoptotic cells in lymphoid tissue exceeded the numbers of productively infected cells, suggesting the occurrence of bystander cell death.40
The best-studied mechanism of bystander cell death in HIV infection is mediated by the binding of envelope glycoprotein (Env) to its cellular receptors (CD4 and a chemokine coreceptor), prior to viral fusion and entry. Apoptosis occurs in the absence of viral replication when infected and uninfected cells are cultured together.45,46 These data suggest that viral proteins interact with uninfected cells and induce an apoptotic signal. The binding of HIV-1 Env to CD4 and CXCR4 (the chemokine receptor utilized by T cell line-tropic HIV) or CCR5 (the chemokine receptor utilized by macrophage-tropic HIV) has been shown to induce apoptosis in primary T lymphocytes.47 Env exerts an inhibitory effect when cells are in the G0/G1 phase of the cell cycle.48 Thus, naïve T cells (CD45RA cells) may be the most affected by Env mediated negative signaling. Interestingly, binding of HIV virions to CD45RA cells decreased mitogenic responses and induced activation-induced cell death (AICD), while memory T cells (CD45RO cells) were less affected.49 Furthermore, cell cycle arrest at the G1/S restriction point was seen only in CD45RA cells following binding of HIV virions.
Binding of Env to CD4 and to a coreceptor activated caspase-3 and caspase-6, and induced cleavage of focal adhesion kinase (FAK).47,50 Cleavage of FAK by caspase-3 and caspase-6 leads to the disassembly of focal adhesion complexes and programmed cell death.51,52 It appears that while CXCR4 induced apoptosis is dependent upon caspase-3 activation, it is insensitive to pertussis toxin and does not involve the activation of the p38MAPK or JNK.50 Activation of caspase-3 and caspase-6 was induced by HIV-1 macrophage tropic Env in PBL from a CCR5Δ32 donor (which have a non-functional coreceptor, due to a CCR5 deletion), suggesting that CD4 receptor engagement is sufficient to provide the stimulus for apoptosis.47 Caspases have been implicated in HIV-mediated apoptosis53 and patients with progressive HIV disease demonstrate increased caspase-3 activity.54 Caspase-3 has been shown to mediate cleavage of Bcl-2 and promotes apoptosis.55 Interestingly, it has been reported that CD4 ligation decreases Bcl-2 expression and induces apoptosis.56 Bcl-2 downregulation was observed in cultured CD4+ T cells, CD8+ T cells and B cells from HIV+ individuals.57 Thus, multiple signaling pathways appear to contribute to the apoptosis induced by ligation of the CD4 receptor.
Recently, we have shown that increases in JAK3 expression and JAK3 activation induced by antigen receptor ligation are inhibited by prior CD4 ligation by HIV gp120 or anti-CD4 mAb.58 The JAK3/STAT5 signaling pathway has been shown to play a major role in the development, proliferation, and survival of T cells59,60,61 (and reviewed in62,63). In vivo evidence for inhibition of the JAK-STAT pathway in HIV disease comes from data of Pericle et al.64 The authors observed a selective reduction of STAT5B expression in HIV infected PBMC and reduced expression of STAT1α, STAT5A and STAT5B in T cells from HIV seropositive individuals. These data argue that T cell dysfunction and apoptosis in HIV disease may be due, in part, to aberrant regulation of the JAK3/STAT5 signaling pathway.
HIV-1 Tat protein has been shown to induce cell death by apoptosis in a T cell line and in cultured peripheral blood mononuclear cells from uninfected controls.65 This Tat-induced apoptosis was inhibitable by growth factors and was associated with enhanced activation of cyclin-dependent kinases. Tat is secreted from infected cells66 and may upregulate FasL on uninfected cells.20 These cells could then either kill themselves by binding Fas expressed on the same cell or kill another cell that has upregulated Fas. In addition, McCloskey et al. reported that addition of exogenous Tat induced apoptosis in Jurkat cells.67 Finally, it has been suggested that Tat binds to cell surface molecules, possibly to CD26 and the integrin, α5β1, both of which transduce apoptotic signals.68,69,70
One mechanism of CD8+ T cell death in HIV disease, as reported by Herbein et al., is dependent upon macrophages.71 These authors showed that ligation of CXCR4 increased membrane bound TNF on macrophages and TNFRII on CD8+ T cells. The interaction between TNF and TNFRII induced death of the CD8+ T cells. As discussed above, secreted Tat could also induce apoptosis of CD8+ T cells. Thus, as described previously for CD4+ T cells, there are multiple mechanisms of CD8+ T cell death in HIV disease (Figure 2).
Inhibition of apoptosis by HIV
HIV may kill the CD4+ T cell that it infects in vivo (as discussed above). However, emerging data suggest that HIV and SIV have evolved mechanisms of blocking or delaying the cellular suicide program. As has been described for many other viral infections,72 it may be beneficial for HIV to inhibit cellular apoptosis, at least until high levels of progeny virus are produced. As discussed below, several HIV-1 gene products have been shown to have anti-apoptotic activity, at least in vitro, and expression of known anti-apoptotic genes (i.e. E1B 19K or a caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone [z-VAD-fmk]) in HIV-1 infected cell lines increases virus production.73,74 In fact, recent studies demonstrating the persistence of latent or low level HIV-1 infection in vivo, in the face of intense anti-retroviral therapy,75 argue that not all infected cells die.
A first line of defense for HIV against cellular apoptosis would be to reduce the levels of surface CD4, to prevent infection by new viruses (‘super-infection interference’), and to inhibit binding and negative signaling by soluble or cellular gp120. At least three HIV-encoded proteins, Nef, Env, and Vpu, contribute to the down-regulation of CD4. Nef, a protein predominantly expressed early in infection, reduces the level of CD4 on the surface by inducing endocytosis.76 Env binds CD4 in the endoplasmic reticulum and thereby inhibits expression.77 Vpu, a protein expressed late in the viral life cycle, facilitates the degradation of CD4 by binding to a cellular factor, h-βTrCP, and targets CD4 for ubiquitin-mediated proteolysis.78,79
Nef has been shown to inhibit T cell activation pathways by interaction with cellular signal transduction proteins [reviewed in 80]. Nef binds to p56lck and inhibits its kinase activity.81 In addition, recent data show that Nef binds to TCR ξ-chain, resulting in downmodulation from the cell surface.82 Both p56lck and TCR ξ-chain are required for downstream events of T cell signal transduction. Thus, the interaction of Nef with p56lck and TCR ξ-chain may prevent AICD of HIV infected cells.83,84 In related studies, Xu et al. have shown that Nef binds to TCR ξ-chain and increases FasL expression.85 The authors suggest that Nef binds to TCR, initiating signaling and upregulation of FasL, without the requirement for antigen engagement. Nef has also been shown to reduce MHC class I on the surface by inducing endocytosis.86 Downregulation of MHC class I and upregulation of FasL by HIV-1 and SIV Nef may protect infected cells from CTL mediated lysis.86,87
Nef has also been reported to bind to p5383 and Tat decreases transcription of p53.88 Downregulation of p53 and inactivation of p53 regulatory functions may promote cell cycle progression, inhibit apoptosis, and produce cell transformation. Recently, Clark et al. reported that HIV infected T cells bypass the G1/S checkpoint by inhibiting p21Waf1, a known cyclin dependent kinase inhibitor.89 This inhibition is mediated by the binding of p53 by Tat, and sequestration of its transactivation activity. The authors postulate that this loss of the G1/S checkpoint provides a selective advantage for HIV by allowing virus associated transcription and production of virions, processes which require T cell cycling.
As discussed above, Vpr has been shown, in some systems, to induce T cell apoptosis. In contrast, low level constitutive expression of Vpr has been shown to inhibit apoptosis by up-regulation of Bcl-2 and down modulation of Bax.90 While non-physiologic or ectopic expression of Vpr may explain these contradictory findings, it is possible that early in infection, low levels of Vpr protect cells from apoptosis, allowing the cells to increase virus production (Figure 3).
Our own work has shown that T cells productively infected with HIV-1 IIIB undergo less apoptosis than control uninfected T cells.91 This relative paucity of apoptosis is characteristic of IIIB infection, since a large number of cells infected with the viral clone, HIV-1 NL4-3, are apoptotic. Mapping studies of IIIB and NL4-3 have not revealed the gene product(s) responsible for this marked difference in the death of infected cells, and the mechanism of inhibition of apoptosis by IIIB is not known. Of interest, Bottarel et al. reported that Env from IIIB does not induce CD4 lateral association with Fas, while Env from the apoptosis-inducing strains 451 and MN induces this association.92 In related studies, we have shown that productive infection with HIV-1 NL4-3, but not IIIB, inhibits JAK3/STAT5 activation, a signaling pathway required for normal T cell function and survival (Selliah and Finkel, manuscript submitted). We hypothesize that activation of the JAK3/STAT5 pathway protects IIIB infected cells from apoptosis, possibly via activation of the anti-apoptotic targets of JAK3, PI3 kinase and Akt.93
Finally, and of most relevance to in vivo infection, we have analyzed apoptosis and HIV-1 RNA in lymph nodes from HIV infected individuals. Lymphoid tissue is a major reservoir of viral infection in HIV disease and a primary site of antigen presentation and lymphocyte activation. Surprisingly, apoptosis is seen predominantly in uninfected bystander cells and not in productively infected cells,43 suggesting that infected cells are relatively protected from apoptosis in vivo. While our in vitro work comparing IIIB and NL4-3 did not analyze primary viral isolates, it is intriguing to speculate that these isolates behave like IIIB and inhibit apoptosis in infected cells. Furthermore, we speculate that, as in other viral infections, ‘attenuated’ HIV is a virus that kills its host cell, having lost or mutated putative anti-apoptotic genes. Viral or cellular targets that inhibit apoptosis, thereby promoting the survival and persistence of HIV-infected cells, may be attractive targets for future therapeutics.
Does current therapy inhibit T cell apoptosis in HIV disease?
In the early stages of HIV disease, CD4+ and CD8+ naïve T cells decline, while CD8+ memory T cells expand.94 At least one study suggests that naïve T cells are more susceptible to HIV induced bystander cell death.49 In the later stages of HIV disease, both CD4+ and CD8+ memory T cells decline at similar rates. Within weeks after administration of highly active anti-retroviral therapy (HAART; combination therapy, in general including at least one protease inhibitor and two other anti-retroviral agents), CD4+ and CD8+ memory T cell populations increase, although significant increases in naïve cells have not been seen.94,95 Alteration of the CD4+ T cell repertoire is not immediately corrected by anti-retroviral and/or immune-based (IL-2) therapy,96 although several studies have shown that administration of IL-2 boosts CD4+ T cell number and function, when used in conjunction with anti-retroviral therapy.96,97,98,99 These studies showed that late expansion of naïve CD4+ T cells was more pronounced with IL-2 plus HAART than with HAART alone. Furthermore, a recent study showed that while HAART plus IL-2 did not decrease spontaneous apoptosis or AICD, there was a delayed and significant increase in CD4+ naïve T cells.99 Since IL-2 did not decrease apoptosis, it has been suggested that the increase in naïve T cells may be due to restoration of thymic function or to increased cellular proliferation.99 However, only PBL were analyzed in this study, leaving open the possibility that a decrease in apoptosis in lymphoid tissue led to the increase in naïve T cell numbers. In fact, Pandolfi et al. reported that intermittent low dose IL-2 with HAART decreased spontaneous apoptosis and increased the number of CD4+ T cells.100 Other studies have shown that anti-retroviral drugs given with IL-2 significantly elevated CD45RO and CD45RA cell numbers and decreased plasma viral load.97,101 In addition, CD45RA cells recovered the ability to produce IL-2, IL-4 and IFN-gamma in vitro, suggesting that treated individuals might have an improved immune response.97 Collectively, these studies show that the combined use of anti-retroviral drugs and IL-2 may be effective in decreasing viral load, increasing CD4+ T cell numbers, and improving immune system function.
Kovacs et al. reported that intermittent courses of IL-2 (with one anti-retroviral drug) increased CD4 numbers by 50% in HIV patients with CD4 counts higher than 200 per mm3, but found only minor improvement in patients with low CD4 counts.102 IL-2 therapy in patients with low CD4 counts was associated with increased viral replication, but few immunologic improvements.102 These data suggest that the use of IL-2 with anti-retroviral drugs may activate resting T cells that harbor replication-competent HIV. A recent report showed that three patients treated with continuous HAART and intermittent IL-2 had significantly fewer resting CD4+ T cells harboring replication-competent HIV RNA.103 IL-2 therapy with anti-retroviral drugs not only activates the immune system and, possibly, HIV from latently infected cells, but also, interestingly, decreases the plasma viral load in some patients.104 These studies are encouraging, although more patients and long term monitoring are required before definitive conclusions can be drawn.
IL-2 prevents apoptosis of CD4+ T cells from HIV seropositive individuals in vitro, and this is correlated with increased Bcl-2 expression.57 Interestingly, IL-15, another γc (the common γ chain on IL-2, IL-4, IL-7, IL-9 and IL-15 cytokine receptors) related cytokine, decreased spontaneous apoptosis of T cells from HIV infected individuals.105 This inhibition of apoptosis was associated with upregulation of Bcl-2 expression. As discussed above, γc related cytokines may prevent spontaneous apoptosis by activation of the JAK3/STAT5 pathway and by upregulation of survival proteins, such as Bcl-2 and Bcl-xL. Thus, signaling through γc may protect bystander cells from Env mediated apoptosis and facilitate reconstitution of the T cell immune system. We hypothesize that γc cytokines, related to but less toxic than IL-2, or selective activation of JAK3, may provide valuable therapeutic tools. In combination with aggressive anti-retroviral therapy, therapies that boost the immune system could significantly delay progression of HIV disease.
Abbreviations
- TNF:
-
tumor necrosis factor
- PBL:
-
peripheral blood lymphocytes
- FAK:
-
focal adhesion kinase
- HIV:
-
human immuno-deficiency virus
References
Daar ES, Moudgil T, Meyer RD and Ho DD . 1991 Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. N. Engl. J. Med. 324: 961–964
Clark SJ, Saag MS, Decker WD, Campbell-Hill S, Roberson JL, Veldkamp PJ, Kappes JC, Hahn BH and Shaw GM . 1991 High titers of cytopathic virus in plasma of patients with symptomatic primary HIV-1 infection. N. Engl. J. Med. 324: 954–960
Piatak MJ, Saag MS, Yang LC, Clark SJ, Kappes JC, Luk KC, Hahn BH, Shaw GM and Lifson JD . 1993 High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 259: 1749–1754
Pantaleo G, Graziosi C and Fauci AS . 1993 New concepts in the immunopathogenesis of human immunodeficiency virus infection. N. Engl. J. Med. 328: 327–335
Mellors JW, Rinaldo Jr CR, Gupta P, White RM, Todd JA and Kingsley LA . 1996 Prognosis in HIV-1 infection predicted by the quantity of virus in plasma [see comments] [published erratum appears in Science 1997 Jan 3;275(5296):14]. Science 272: 1167–1170
Furtado MR, Kingsley LA and Wolinsky SM . 1995 Changes in the viral mRNA expression pattern correlate with a rapid rate of CD4+ T-cell number decline in human immunodeficiency virus type 1-infected individuals. J. Virol. 69: 2092–2100
Gougeon ML, Lecoeur H, Dulioust A, Enouf MG, Crouvoiser M, Goujard C, Debord T and Montagnier L . 1996 Programmed cell death in peripheral lymphocytes from HIV-infected persons: increased susceptibility to apoptosis of CD4 and CD8 T cells correlates with lymphocyte activation and with disease progression. J. Immunol. 156: 3509–3520
Cotton MF, Ikle DN, Rapaport EL, Marschner S, Tseng PO, Kurrle R and Finkel TH . 1997 Apoptosis of CD4+ and CD8+ T cells isolated immediately ex vivo correlates with disease severity in human immunodeficiency virus type 1 infection. Pediatr. Res. 42: 656–664
Hellerstein M, Hanley MB, Cesar D, Siler S, Papageorgopoulos C, Wieder E, Schmidt D, Hoh R, Neese R, Macallan D, Deeks S and McCune JM . 1999 Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans [see comments]. Nat. Med. 5: 83–89
Fleury S, de Boer RJ, Rizzardi GP, Wolthers KC, Otto SA, Welbon CC, Graziosi C, Knabenhans C, Soudeyns H, Bart PA, Gallant S, Corpataux JM, Gillet M, Meylan P, Schnyder P, Meuwly JY, Spreen W, Glauser MP, Miedema F and Pantaleo G . 1998 Limited CD4+ T-cell renewal in early HIV-1 infection: effect of highly active antiretroviral therapy. Nat. Med. 4: 794–801
Brunner T, Mogil RJ, LaFace D, Yoo NJ, Mahboubi A, Echeverri F, Martin SJ, Force WR, Lynch DH, Ware CF and Green DR. . 1995 Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas [see comments]. Nature 373: 441–444
Dhein J, Walczak H, Baumler C, Debatin KM and Krammer PH . 1995 Autocrine T-cell suicide mediated by APO-1/(Fas/CD95) [see comments]. Nature 373: 438–441
Ju ST, Panka DJ, Cui H, Ettinger R, el-Khatib M, Sherr DH, Stanger BZ and Marshak-Rothstein A . 1995 Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation [see comments]. Nature 373: 444–448
Kaplan D and Sieg S . 1998 Role of the Fas/Fas ligand apoptotic pathway in human immunodeficiency virus type 1 disease. J. Virol. 72: 6279–6282
Jaworowski A and Crowe SM . 1999 Does HIV cause depletion of CD4+ T cells in vivo by the induction of apoptosis? Immunol. Cell Biol. 77: 90–98
Silvestris F, Cafforio P, Frassanito MA, Tucci M, Romito A, Nagata S and Dammacco F . 1996 Overexpression of Fas antigen on T cells in advanced HIV-1 infection: differential ligation constantly induces apoptosis. AIDS 10: 131–141
Aries SP, Schaaf B, Muller C, Dennin RH and Dalhoff K . 1995 Fas (CD95) expression on CD4+ T cells from HIV-infected patients increases with disease progression. J. Mol. Med. 73: 591–593
Katsikis PD, Wunderlich ES, Smith CA and Herzenberg LA . 1995 Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals. J. Exp. Med. 181: 2029–2036
Casella CR, Rapaport EL and Finkel TH . 1999 Vpu increases susceptibility of human immunodeficiency virus type 1-infected cells to fas killing. J. Virol. 73: 92–100
Westendorp MO, Frank R, Ochsenbauer C, Stricker K, Dhein J, Walczak H, Debatin KM and Krammer PH . 1995 Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 375: 497–500
Bartz SR and Emerman M . 1999 Human immunodeficiency virus type 1 Tat induces apoptosis and increases sensitivity to apoptotic signals by up-regulating FLICE/caspase-8. J. Virol. 73: 1956–1963
Zauli G, Gibellini D, Secchiero P, Dutartre H, Olive D, Capitani S and Collette Y . 1999 Human immunodeficiency virus type 1 Nef protein sensitizes CD4(+) T lymphoid cells to apoptosis via functional upregulation of the CD95/CD95 ligand pathway. Blood 93: 1000–1010
Manna SK and Aggarwal BB . 2000 Differential requirement for p56lck in HIV-tat versus TNF-induced cellular responses: effects on NF-kappaB, activator protein-1, c-Jun N-terminal kinase, and apoptosis [In Process Citation]. J. Immunol. 164: 5156–5166
Jacotot E, Ravagnan L, Loeffler M, Ferri KF, Vieira HL, Zamzami N, Costantini P, Druillennec S, Hoebeke J, Briand JP, Irinopoulou T, Daugas E, Susin SA, Cointe D, Xie ZH, Reed JC, Roques BP and Kroemer G . 2000 The HIV-1 viral protein R induces apoptosis via a direct effect on the mitochondrial permeability transition pore. J. Exp. Med. 191: 33–46
Macho A, Castedo M, Marchetti P, Aguilar JJ, Decaudin D, Zamzami N, Girard PM, Uriel J and Kroemer G . 1995 Mitochondrial dysfunctions in circulating T lymphocytes from human immunodeficiency virus-1 carriers [see comments]. Blood 86: 2481–2487
Re M, Gibellini D, Aschbacher R, Vignoli M, Furlini G, Ramazzotti E, Bertolaso L and La Placa M . 1998 High levels of HIV-1 replication show a clear correlation with downmodulation of Bcl-2 protein in peripheral blood lymphocytes of HIV-1-seropositive subjects. J. Med. Virol. 56: 66–73
Regamey N, Harr T, Battegay M and Erb P . 1999 Downregulation of Bcl-2, but not of Bax or Bcl-x, is associated with T lymphocyte apoptosis in HIV infection and restored by antiretroviral therapy or by interleukin 2. AIDS Res. Hum. Retrovir. 15: 803–810
Sastry KJ, Marin MC, Nehete PN, McConnell K, el-Naggar AK and McDonnell TJ . 1996 Expression of human immunodeficiency virus type I tat results in down-regulation of bcl-2 and induction of apoptosis in hematopoietic cells. Oncogene 13: 487–493
Strack PR, Frey MW, Rizzo CJ, Cordova B, George HJ, Meade R, Ho SP, Corman J, Tritch R and Korant BD . 1996 Apoptosis mediated by HIV protease is preceded by cleavage of Bcl-2. Proc. Natl. Acad. Sci. U.S.A. 93: 9571–9576
Korant BD, Strack P, Frey MW and Rizzo CJ . 1998 A cellular anti-apoptosis protein is cleaved by the HIV-1 protease. Adv. Exp. Med. Biol. 436: 27–29
Nosaka T, Kawashima T, Misawa K, Ikuta K, Mui AL and Kitamura T . 1999 STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells. EMBO J. 18: 4754–4765
Horita M, Andreu EJ, Benito A, Arbona C, Sanz C, Benet I, Prosper F and Fernandez-Luna JL . 2000 Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-xL. J. Exp. Med. 191: 977–984
Poon B, Grovit-Ferbas K, Stewart SA and Chen ISnY . 1998 Cell cycle arrest by Vpr in HIV-1 virions and insensitivity to antiretroviral agents. Science 281: 266–269
He J, Choe S, Walker R, Di Marzio P, Morgan DO and Landau NR . 1995 Human immunodeficiency virus type 1 viral protein R (Vpr) arrests cells in the G2 phase of the cell cycle by inhibiting p34cdc2 activity. J. Virol. 69: 6705–6711
Re F, Braaten D, Franke EK and Luban J . 1995 Human immunodeficiency virus type 1 Vpr arrests the cell cycle in G2 by inhibiting the activation of p34cdc2-cyclin. B. J. Virol. 69: 6859–6864
Hrimech M, Yao XJ, Branton PE and Cohen EA . 2000 Human immunodeficiency virus type 1 Vpr-mediated G(2) cell cycle arrest: Vpr interferes with cell cycle signaling cascades by interacting with the B subunit of serine/threonine protein phosphatase 2A. EMBO J. 19: 3956–3967
Nishizawa M, Kamata M, Katsumata R and Aida Y . 2000 A carboxy-terminally truncated form of the human immunodeficiency virus type 1 Vpr protein induces apoptosis via G(1) cell cycle arrest. J. Virol. 74: 6058–6067
Stewart SA, Poon B, Song JY and Chen IS . 2000 Human immunodeficiency virus type 1 vpr induces apoptosis through caspase activation. J. Virol. 74: 3105–3111
Embretson J, Zupancic M, Ribas JL, Burke A, Racz P, Tenner-Racz K and Haase AT . 1993 Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS [see comments]. Nature 362: 359–362
Carbonari M, Cibati M, Pesce AM, Sbarigia D, Grossi P, D'Offizi G, Luzi G and Fiorilli M . 1995 Frequency of provirus-bearing CD4+ cells in HIV type 1 infection correlates with extent of in vitro apoptosis of CD8+ but not of CD4+ cells. AIDS Res. Hum. Retrovir. 11: 789–794
Bofill M, Gombert W, Borthwick NJ, Akbar AN, McLaughlin JE, Lee CA, Johnson MA, Pinching AJ and Janossy G . 1995 Presence of CD3+CD8+Bcl-2(low) lymphocytes undergoing apoptosis and activated macrophages in lymph nodes of HIV-1+ patients. Am. J. Pathol. 146: 1542–1555
Cotton MF, Cassella C, Rapaport EL, Tseng PO, Marschner S and Finkel TH . 1996 Apoptosis in HIV-1 Infection. Behring Inst. Mitt. 220–231
Finkel TH, Tudor-Williams G, Banda NK, Cotton MF, Curiel T, Monks C, Baba TW, Ruprecht RM and Kupfer A . 1995 Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes [see comments]. Nat. Med. 1: 129–134
Zhang ZQ, Notermans DW, Sedgewick G, Cavert W, Wietgrefe S, Zupancic M, Gebhard K, Henry K, Boies L, Chen Z, Jenkins M, Mills R, McDade H, Goodwin C, Schuwirth CM, Danner SA and Haase AT . 1998 Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection. Proc. Natl. Acad. Sci. U.S.A. 95: 1154–1159
Nardelli B, Gonzalez CJ, Schechter M and Valentine FT . 1995 CD4+ blood lymphocytes are rapidly killed in vitro by contact with autologous human immunodeficiency virus-infected cells. Proc. Natl. Acad. Sci. U.S.A. 92: 7312–7316
Heinkelein M, Sopper S and Jassoy C . 1995 Contact of human immunodeficiency virus type 1-infected and uninfected CD4+ T lymphocytes is highly cytolytic for both cells. J. Virol. 69: 6925–6931
Cicala C, Arthos J, Rubbert A, Selig S, Wildt K, Cohen OJ and Fauci AS . 2000 HIV-1 envelope induces activation of caspase-3 and cleavage of focal adhesion kinase in primary human CD4(+) T cells. Proc. Natl. Acad. Sci. U.S.A. 97: 1178–1183
Gratton S, Julius M and Sekaly RP . 1998 lck-independent inhibition of T cell antigen response by the HIV gp120. J. Immunol. 161: 3551–3556
Masci AM, Paz FL, Borriello A, Cassano S, Della Pietra V, Stoiber H, Matarese G, Della Ragione F, Zappacosta S and Racioppi L . 1999 Effects of human immunodeficiency virus type 1 on CD4 lymphocyte subset activation. Eur. J. Immunol. 29: 1879–1889
Biard-Piechaczyk M, Robert-Hebmann V, Richard V, Roland J, Hipskind RA and Devaux C . 2000 Caspase-dependent apoptosis of cells expressing the chemokine receptor CXCR4 is induced by cell membrane-associated human immunodeficiency virus type 1 envelope glycoprotein (gp120). Virology 268: 329–344
Gervais FG, Thornberry NA, Ruffolo SC, Nicholson DW and Roy S . 1998 Caspases cleave focal adhesion kinase during apoptosis to generate a FRNK-like polypeptide. J. Biol. Chem. 273: 17102–17108
Wen LP, Fahrni JA, Troie S, Guan JL, Orth K and Rosen GD . 1997 Cleavage of focal adhesion kinase by caspases during apoptosis. J. Biol. Chem. 272: 26056–26061
Katsikis PD, Garcia-Ojeda ME, Torres-Roca JF, Tijoe IM, Smith CA and Herzenberg LA . 1997 Interleukin-1 beta converting enzyme-like protease involvement in Fas- induced and activation-induced peripheral blood T cell apoptosis in HIV infection. TNF-related apoptosis-inducing ligand can mediate activation-induced T cell death in HIV infection. J. Exp. Med. 186: 1365–1372
Liegler TJ, Yonemoto W, Elbeik T, Vittinghoff E, Buchbinder SP and Greene WC . 1998 Diminished spontaneous apoptosis in lymphocytes from human immunodeficiency virus-infected long-term nonprogressors. J. Infect. Dis. 178: 669–679
Kirsch DG, Doseff A, Chau BN, Lim DS, de Souza-Pinto NC, Hansford R, Kastan MB, Lazebnik YA and Hardwick JM . 1999 Caspase-3-dependent cleavage of Bcl-2 promotes release of cytochrome c. J. Biol. Chem. 274: 21155–21161
Hashimoto F, Oyaizu N, Kalyanaraman VS and Pahwa S . 1997 Modulation of Bcl-2 protein by CD4 cross-linking: a possible mechanism for lymphocyte apoptosis in human immunodeficiency virus infection and for rescue of apoptosis by interleukin-2. Blood 90: 745–753
Adachi Y, Oyaizu N, Than S, McCloskey TW and Pahwa S . 1996 IL-2 rescues in vitro lymphocyte apoptosis in patients with HIV infection: correlation with its ability to block culture-induced down- modulation of Bcl-2. J. Immunol. 157: 4184–4193
Selliah N and Finkel TH . 1998 Cutting edge: JAK3 activation and rescue of T cells from HIV gp120- induced unresponsiveness. J. Immunol. 160: 5697–5701
Suzuki K, Nakajima H, Saito Y, Saito T, Leonard WJ and Iwamoto I . 2000 Janus kinase 3 (Jak3) is essential for common cytokine receptor gamma chain (gamma(c))-dependent signaling: comparative analysis of gamma(c), Jak3, and gamma(c) and Jak3 double-deficient mice. Int. Immunol. 12: 123–132
Thomis DC, Lee W and Berg LJ . 1997 T cells from Jak3-deficient mice have intact TCR signaling, but increased apoptosis. J. Immunol. 159: 4708–4719
Moriggl R, Sexl V, Piekorz R, Topham D and Ihle JN . 1999 Stat5 activation is uniquely associated with cytokine signaling in peripheral T cells. Immunity. 11: 225–230
Darnell Jr JE . 1997 STATs and gene regulation. Science 277: 1630–1635
O'Shea JJ . 1997 Jaks, STATs, cytokine signal transduction and immunoregulation: are we there yet? [published erratum appears in Immunity 1997 Sep;7(3):following 444]. Immunity 7: 1–11
Pericle F, Pinto LA, Hicks S, Kirken RA, Sconocchia G, Rusnak J, Dolan MJ, Shearer GM and Segal DM . 1998 HIV-1 infection induces a selective reduction in STAT5 protein expression. J. Immunol. 160: 28–31
Li CJ, Friedman DJ, Wang C, Metelev V and Pardee AB . 1995 Induction of apoptosis in uninfected lymphocytes by HIV-1 Tat protein. Science 268: 429–431
Ensoli B, Barillari G, Salahuddin SZ, Gallo RC and Wong-Staal F . 1990 Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients. Nature 345: 84–86
McCloskey TW, Ott M, Tribble E, Khan SA, Teichberg S, Paul MO, Pahwa S, Verdin E and Chirmule N . 1997 Dual role of HIV Tat in regulation of apoptosis in T cells. J. Immunol. 158: 1014–1019
Gutheil WG, Subramanyam M, Flentke GR, Sanford DG, Munoz E, Huber BT and Bachovchin WW . 1994 Human immunodeficiency virus 1 Tat binds to dipeptidyl aminopeptidase IV (CD26): a possible mechanism for Tat's immunosuppressive activity. Proc. Natl. Acad. Sci. U.S.A. 91: 6594–6598
Morimoto C, Lord CI, Zhang C, Duke-Cohan JS, Letvin NL and Schlossman SF . 1994 Role of CD26/dipeptidyl peptidase IV in human immunodeficiency virus type 1 infection and apoptosis. Proc. Natl. Acad. Sci. U.S.A. 91: 9960–9964
Zhang Z, Vuori K, Reed JC and Ruoslahti E . 1995 The alpha 5 beta 1 integrin supports survival of cells on fibronectin and up-regulates Bcl-2 expression. Proc. Natl. Acad. Sci. U.S.A. 92: 6161–6165
Herbein G, Mahlknecht U, Batliwalla F, Gregersen P, Pappas T, Butler J, O'Brien WA and Verdin E . 1998 Apoptosis of CD8+ T cells is mediated by macrophages through interaction of HIV gp120 with chemokine receptor CXCR4 [see comments]. Nature 395: 189–194
Krajcsi P and Wold WS . 1998 Viral proteins that regulate cellular signalling. J. Gen. Virol. 79: 1323–1335
Antoni BA, Sabbatini P, Rabson AB and White E . 1995 Inhibition of apoptosis in human immunodeficiency virus-infected cells enhances virus production and facilitates persistent infection. J. Virol. 69: 2384–2392
Chinnaiyan AM, Woffendin C, Dixit VM and Nabel GJ . 1997 The inhibition of pro-apoptotic ICE-like proteases enhances HIV replication. Nat. Med. 3: 333–337
Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, Smith K, Lisziewicz J, Lori F, Flexner C, Quinn TC, Chaisson RE, Rosenberg E, Walker B, Gange S, Gallant J and Siliciano RF . 1999 Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy [see comments]. Nat. Med. 5: 512–517
Salghetti S, Mariani R and Skowronski J . 1995 Human immunodeficiency virus type 1 Nef and p561ck protein-tyrosine kinase interact with a common element in CD4 cytoplasmic tail. Proc. Natl. Acad. Sci. U.S.A. 92: 349–353
Crise B, Buonocore L and Rose JK . 1990 CD4 is retained in the endoplasmic reticulum by the human immunodeficiency virus type 1 glycoprotein precursor. J. Virol. 64: 5585–5593
Willey RL, Maldarelli F, Martin MA and Strebel K . 1992 Human immunodeficiency virus type 1 Vpu protein induces rapid degradation of CD4. J. Virol. 66: 7193–7200
Margottin F, Bour SP, Durand H, Selig L, Benichou S, Richard V, Thomas D, Strebel K and Benarous R . 1998 A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. Mol. Cell. 1: 565–574
Greenway A and McPhee D . 1997 HIV1 Nef: the Machiavelli of cellular activation. Res. Virol. 148: 58–64
Greenway A, Azad A, Mills J and McPhee D . 1996 Human immunodeficiency virus type 1 Nef binds directly to Lck and mitogen-activated protein kinase, inhibiting kinase activity. J. Virol. 70: 6701–6708
Schaefer TM, Bell I, Fallert BA and Reinhart TA . 2000 The T-cell receptor zeta chain contains two homologous domains with which simian immunodeficiency virus Nef interacts and mediates down-modulation. J. Virol. 74: 3273–3283
Greenway A, Azad A and McPhee D . 1995 Human immunodeficiency virus type 1 Nef protein inhibits activation pathways in peripheral blood mononuclear cells and T-cell lines. J. Virol. 69: 1842–1850
Combadiere B, Freedman M, Chen L, Shores EW, Love P and Lenardo MJ . 1996 Qualitative and quantitative contributions of the T cell receptor zeta chain to mature T cell apoptosis. J. Exp. Med. 183: 2109–2117
Xu XN, Laffert B, Screaton GR, Kraft M, Wolf D, Kolanus W, Mongkolsapay J, McMichael AJ and Baur AS . 1999 Induction of Fas ligand expression by HIV involves the interaction of Nef with the T cell receptor zeta chain. J. Exp. Med. 189: 1489–1496
Schwartz O, Marechal V, Le Gall S, Lemonnier F and Heard JM . 1996 Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. Nat. Med. 2: 338–342
Collins KL, Chen BK, Kalams SA, Walker BD and Baltimore D . 1998 HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391: 397–401
Li CJ, Wang C, Friedman DJ and Pardee AB . 1995 Reciprocal modulations between p53 and Tat of human immunodeficiency virus type 1. Proc. Natl. Acad. Sci. U.S.A. 92: 5461–5464
Clark E, Santiago F, Deng L, Chong S, de La Fuente C, Wang L, Fu P, Stein D, Denny T, Lanka V, Mozafari F, Okamoto T and Kashanchi F . 2000 Loss of G(1)/S checkpoint in human immunodeficiency virus type 1-infected cells is associated with a lack of cyclin-dependent kinase inhibitor p21/Waf1 [In Process Citation]. J. Virol. 74: 5040–5052
Conti L, Rainaldi G, Matarrese P, Varano B, Rivabene R, Columba S, Sato A, Belardelli F, Malorni W and Gessani S . 1998 The HIV-1 vpr protein acts as a negative regulator of apoptosis in a human lymphoblastoid T cell line: possible implications for the pathogenesis of AIDS. J. Exp. Med. 187: 403–413
Rapaport E, Casella CR, Ikle D, Mustafa F, Isaak D and Finkel TH . 1998 Mapping of HIV-1 determinants of apoptosis in infected T cells. Virology 252: 407–417
Bottarel F, Feito MJ, Bragardo M, Bonissoni S, Buonfiglio D, DeFranco S, Malavasi F, Bensi T, Ramenghi U and Dianzani U . 1999 The cell death-inducing ability of glycoprotein 120 from different HIV strains correlates with their ability to induce CD4 lateral association with CD95 on CD4+ T cells. AIDS Res. Hum. Retrovir. 15: 1255–1263
Sharfe N, Dadi HK and Roifman CM . 1995 JAK3 protein tyrosine kinase mediates interleukin-7-induced activation of phosphatidylinositol-3′ kinase. Blood 86: 2077–2085
Roederer M, Dubs JG, Anderson MT, Raju PA and Herzenberg LA . 1995 CD8 naive T cell counts decrease progressively in HIV-infected adults. J. Clin. Invest. 95: 2061–2066
Pakker NG, Notermans DW, de Boer RJ, Roos MT, de Wolf F, Hill A, Leonard JM, Danner SA, Miedema F and Schellekens PT . 1998 Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation [see comments]. Nat. Med. 4: 208–214
Connors M, Kovacs JA, Krevat S, Gea-Banacloche JC, Sneller MC, Flanigan M, Metcalf JA, Walker RE, Falloon J, Baseler M, Feuerstein I, Masur H and Lane HC . 1997 HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies [see comments]. Nat. Med. 3: 533–540
De Paoli P, Zanussi S, Simonelli C, Bortolin MT, D'Andrea M, Crepaldi C, Talamini R, Comar M, Giacca M and Tirelli U . 1997 Effects of subcutaneous interleukin-2 therapy on CD4 subsets and in vitro cytokine production in HIV+ subjects. J. Clin. Invest. 100: 2737–2743
Emery S and Lane HC . 1997 Immune reconstitution in HIV infection [see comments]. Curr. Opin. Immunol. 9: 568–572
Caggiari L, Zanussi S, Bortolin MT, D'Andrea M, Nasti G, Simonelli C, Tirelli U and De Paoli P . 2000 Effects of therapy with highly active anti-retroviral therapy (HAART) and IL-2 on CD4+ and CD8+ lymphocyte apoptosis in HIV+ patients. Clin. Exp. Immunol. 120: 101–106
Pandolfi F, Pierdominici M, Marziali M, Livia Bernardi M, Antonelli G, Galati V, D'Offizi G and Aiuti F . 2000 Low-dose IL-2 reduces lymphocyte apoptosis and increases naive CD4 cells in HIV-1 patients treated with HAART. Clin. Immunol. 94: 153–159
Simonelli C, Zanussi S, Sandri S, Comar M, Lucenti A, Talamini R, Bortolin MT, Giacca M, De Paoli P and Tirelli U . 1999 Concomitant therapy with subcutaneous interleukin-2 and zidovudine plus didanosine in patients with early stage HIV infection. J. Acquir. Immune. Defic. Syndr. Hum. Retrovirol. 20: 20–27
Kovacs JA, Baseler M, Dewar RJ, Vogel S, Davey Jr RT, Falloon J, Polis MA, Walker RE, Stevens R, Salzman NP, Metcalf JA, Masur H and Lane CH. . 1995 Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection. A preliminary study [see comments]. N. Engl. J. Med. 332: 567–575
Chun TW, Engel D, Mizell SB, Hallahan CW, Fischette M, Park S, Davey Jr RT, Dybul M, Kovacs JA, Metcalf JA, Mican JM, Berrey MM, Corey L, Lane HC and Fauci AS . 1999 Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-retroviral therapy [see comments]. Nat. Med. 5: 651–655
Zanussi S, Simonelli C, Bortolin MT, D'Andrea M, Comar M, Tirelli U, Giacca M and De Paoli P . 1999 Dynamics of provirus load and lymphocyte subsets after interleukin 2 treatment in HIV-infected patients. AIDS Res. Hum. Retrovir. 15: 97–103
Naora H and Gougeon ML . 1999 Interleukin-15 is a potent survival factor in the prevention of spontaneous but not CD95-induced apoptosis in CD4 and CD8 T lymphocytes of HIV-infected individuals. Correlation with its ability to increase BCL-2 expression. Cell Death Differ. 6: 1002–1011
Kolesnitchenko V, Wahl LM, Tian H, Sunila I, Tani Y, Hartmann DP, Cossman J, Raffeld M, Orenstein J, Samelson LE and Cohen DI. . 1995 Human immunodeficiency virus 1 envelope-initiated G2-phase programmed cell death. Proc. Natl. Acad. Sci. U.S.A. 92: 11889–11893
Oyaizu N, McCloskey TW, Than S, Hu R, Kalyanaraman VS and Pahwa S . 1994 Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-gamma and tumor necrosis factor-alpha secretion. Blood 84: 2622–2631
Corbeil J and Richman DD . 1995 Productive infection and subsequent interaction of CD4-gp120 at the cellular membrane is required for HIV-induced apoptosis of CD4+ T cells. J. Gen. Virol. 76: 681–690
Fermin CD and Garry RF . 1992 Membrane alterations linked to early interactions of HIV with the cell surface. Virology 191: 941–946
Cohen DI, Tani Y, Tian H, Boone E, Samelson LE and Lane HC . 1992 Participation of tyrosine phosphorylation in the cytopathic effect of human immunodeficiency virus-1. Science 256: 542–545
Koga Y, Sasaki M, Yoshida H, Wigzell H, Kimura G and Nomoto K . 1990 Cytopathic effect determined by the amount of CD4 molecules in human cell lines expressing envelope glycoprotein of HIV. J. Immunol. 144: 94–102
Chirmule N, Goonewardena H, Pahwa S, Pasieka R and Kalyanaraman VS . 1995 HIV-1 envelope glycoproteins induce activation of activated protein-1 in CD4+ T cells [published erratum appears in J Biol Chem 1995 Dec 1;270(48):29038]. J. Biol. Chem. 270: 19364–19369
Popik W and Pitha PM . 1996 Binding of human immunodeficiency virus type 1 to CD4 induces association of Lck and Raf-1 and activates Raf-1 by a Ras-independent pathway. Mol. Cell. Biol. 16: 6532–6541
Levy JA . 1993 Pathogenesis of human immunodeficiency virus infection. Microbiol. Rev. 57: 183–289
Cheynier R, Henrichwark S, Hadida F, Pelletier E, Oksenhendler E, Autran B and Wain-Hobson S . 1994 HIV and T cell expansion in splenic white pulps is accompanied by infiltration of HIV-specific cytotoxic T lymphocytes. Cell 78: 373–387
Brenner BG, Gryllis C and Wainberg MA . 1991 Role of antibody-dependent cellular cytotoxicity and lymphokine- activated killer cells in AIDS and related diseases. J. Leukoc. Biol. 50: 628–640
Spear GT, Landay AL, Sullivan BL, Dittel B and Lint TF . 1990 Activation of complement on the surface of cells infected by human immunodeficiency virus. J. Immunol. 144: 1490–1496
Cao J, Park IW, Cooper A and Sodroski J . 1996 Molecular determinants of acute single-cell lysis by human immunodeficiency virus type 1. J. Virol. 70: 1340–1354
Glynn JM, McElligott DL and Mosier DE . 1996 Apoptosis induced by HIV infection in H9 T cells is blocked by ICE- family protease inhibition but not by a Fas(CD95) antagonist. J. Immunol. 157: 2754–2758
Badley AD, McElhinny JA, Leibson PJ, Lynch DH, Alderson MR and Paya CV . 1996 Upregulation of Fas ligand expression by human immunodeficiency virus in human macrophages mediates apoptosis of uninfected T lymphocytes. J. Virol. 70: 199–206
Weinhold KJ, Lyerly HK, Stanley SD, Austin AA, Matthews TJ and Bolognesi DP . 1989 HIV-1 GP120-mediated immune suppression and lymphocyte destruction in the absence of viral infection. J. Immunol. 142: 3091–3097
Foster S, Beverley P and Aspinall R . 1995 gp120-induced programmed cell death in recently activated T cells without subsequent ligation of the T cell receptor. Eur. J. Immunol. 25: 1778–1782
Banda NK, Bernier J, Kurahara DK, Kurrle R, Haigwood N, Sekaly RP and Finkel TH . 1992 Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis. J. Exp. Med. 176: 1099–1106
Radrizzani M, Accornero P, Amidei A, Aiello A, Delia D, Kurrle R and Colombo MP . 1995 IL-12 inhibits apoptosis induced in a human Th1 clone by gp120/CD4 cross-linking and CD3/TCR activation or by IL-2 deprivation. Cell. Immunol. 161: 14–21
Zinkernagel RM and Hengartner H . 1994 T-cell-mediated immunopathology versus direct cytolysis by virus: implications for HIV and AIDS. Immunol. Today 15: 262–268
Effros RB, Allsopp R, Chiu CP, Hausner MA, Hirji K, Wang L, Harley CB, Villeponteau B, West MD and Giorgi JV . 1996 Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis. AIDS 10: F17–F22
Wolthers KC, Bea G, Wisman A, Otto SA, de Roda Husman AM, Schaft N, de Wolf F, Goudsmit J, Coutinho RA, van der Zee AG, Meyaard L and Miedema F . 1996 T cell telomere length in HIV-1 infection: no evidence for increased CD4+ T cell turnover. Science 274: 1543–1547
Estaquier J, Idziorek T, Zou W, Emilie D, Farber CM, Bourez JM and Ameisen JC . 1995 T helper type 1/T helper type 2 cytokines and T cell death: preventive effect of interleukin 12 on activation-induced and CD95 (FAS/APO-1)- mediated apoptosis of CD4+ T cells from human immunodeficiency virus- infected persons. J. Exp. Med. 182: 1759–1767
Caputo A, Sodroski JG and Haseltine WA . 1990 Constitutive expression of HIV-1 tat protein in human Jurkat T cells using a BK virus vector. J. Acquir. Immune Defic. Syndr. 3: 372–379
Zauli G, Gibellini D, Milani D, Mazzoni M, Borgatti P, La Placa M and Capitani S . 1993 Human immunodeficiency virus type 1 Tat protein protects lymphoid, epithelial, and neuronal cell lines from death by apoptosis. Cancer Res. 53: 4481–4485
Gibellini D, Caputo A, Celeghini C, Bassini A, La Placa M, Capitani S and Zauli G . 1995 Tat-expressing Jurkat cells show an increased resistance to different apoptotic stimuli, including acute human immunodeficiency virus-type 1 (HIV-1) infection. Br. J. Haematol. 89: 24–33
Viscidi RP, Mayur K, Lederman HM and Frankel AD . 1989 Inhibition of antigen-induced lymphocyte proliferation by Tat protein from HIV-1. Science 246: 1606–1608
Howcroft TK, Strebel K, Martin MA and Singer DS . 1993 Repression of MHC class I gene promoter activity by two-exon Tat of HIV. Science 260: 1320–1322
Zauli G, Gibellini D, Caputo A, Bassini A, Negrini M, Monne M, Mazzoni M and Capitani S . 1995 The human immunodeficiency virus type-1 Tat protein upregulates Bc1-2 gene expression in Jurkat T-cell lines and primary peripheral blood mononuclear cells. Blood 86: 3823–3834
Collette Y, Dutartre H, Benziane A, Ramos M, Benarous R, Harris M and Olive D . 1996 Physical and functional interaction of Nef with Lck. HIV-1 Nef-induced T-cell signaling defects. J. Biol. Chem. 271: 6333–6341
Saksela K, Cheng G and Baltimore D . 1995 Proline-rich (PxxP) motifs in HIV-1 Nef bind to SH3 domains of a subset of Src kinases and are required for the enhanced growth of Nef+ viruses but not for down-regulation of CD4. EMBO J. 14: 484–491
Jowett JB, Planelles V, Poon B, Shah NP, Chen ML and Chen IS . 1995 The human immunodeficiency virus type 1 vpr gene arrests infected T cells in the G2+M phase of the cell cycle. J. Virol. 69: 6304–6313
Rogel ME, Wu LI and Emerman M . 1995 The human immunodeficiency virus type 1 vpr gene prevents cell proliferation during chronic infection. J. Virol. 69: 882–888
Ayyavoo V, Mahboubi A, Mahalingam S, Ramalingam R, Kudchodkar S, Williams WV, Green DR and Weiner DB . 1997 HIV-1 Vpr suppresses immune activation and apoptosis through regulation of nuclear factor kappa B [see comments]. Nat. Med. 3: 1117–1123
Luban J, Bossolt KL, Franke EK, Kalpana GV and Goff SP . 1993 Human immunodeficiency virus type 1 Gag protein binds to cyclophilins A and B. Cell 73: 1067–1078
Author information
Authors and Affiliations
Corresponding author
Additional information
Edited by J M Hardwick
Rights and permissions
About this article
This article is cited by
-
The cellular autophagy/apoptosis checkpoint during inflammation
Cellular and Molecular Life Sciences (2017)
-
A review of the nondeterministic waiting time algorithm
Natural Computing (2011)
-
Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy
Retrovirology (2008)
-
Actin integrity is indispensable for CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells
Apoptosis (2007)
-
HIV-1 Tat targets Tip60 to impair the apoptotic cell response to genotoxic stresses
The EMBO Journal (2005)