CD4 opens the door

Like an uninvited visitor tricking the host to gain entry, viruses induce ‘door-opening’ cellular processes like endocytosis by engaging the host cell’s surface proteins. Although not intended by the host cell to function as viral entry receptors, these proteins are subverted into a gateway role by the virus.

CD4 was originally described in 1979 by Ellis Reinherz in Stuart Schlossman’s lab as helper T lymphocyte antigen. Four years later, Luc Montagnier’s group reported that HIV-1 was contained within the CD4⁺ T cell fraction isolated from a patient with HIV-1 and selectively infected and depleted CD4⁺ T cells in healthy-donor-derived lymphocyte cultures. The authors postulated HIV-1 tropism for CD4⁺ T cells and speculated that the virus mediates CD4⁺ T cell loss in AIDS. They also noted normal CD4⁺ T cell numbers in one HIV-1-positive individual, raising the question of what factors constitute the in vivo determinants of HIV-1cytopathology, a puzzle that took decades to solve.

In 1984, two seminal studies showed that CD4 is critical forHIV-1 entry. In the absence of HIV-1-specific reagents, Robin Weiss and colleagues postulated CD4’s role as an HIV-1 receptor using two proxy readouts of HIV-1 entry: multinucleated syncytia formation and cell lysis by vesicular stomatitis virus (VSV) virions bearing HIV-1 envelope proteins. This approach was a fortuitous choice, as native HIV-1 entry requires co-receptors unknown at that time (MILESTONE 15). CD4-specific antibodies blocked HIV-1-induced syncytia formation in cell lines. In parallel, Montagnier’s team reported that anti-CD4 antibodies blocked HIV-1 replication in primary T cells. The CD4 gene was cloned in 1985 by Richard Axel and colleagues, who then introduced recombinant CD4 cDNA into HIV-1-resistant CD4-negative cells, conferring susceptibility to virus infection. Together with later characterization of CD4 binding to the HIV-1 envelope glycoprotein gp120, this research led the way to the development of HIV-1 entry-targeting therapies, elucidation of CD4’s role in HIV-1 pathogenesis and characterization of HIV-1 cellular reservoirs.

In the clinic, CD4⁺ T cell depletion was recognized as a hallmark of AIDS from the outset (MILESTONE 13), and a CD4⁺ T cell count of less than 200 cells per microliter of blood is now part of the defining features of AIDS. Although HIV-1 seropositivity was instrumental in determining HIV-1 status, CD4⁺ T cell count remained unrivalled as a quantitative measure of pathology in the era preceding tests for viral RNA load. During that time, CD4⁺ T cell count was the key prognostic factor for immune function loss and an essential biomarker of therapeutic efficacy. To this day, CD4⁺ T cell count informs disease staging and therapeutic choices.

Yet, reliance on CD4 for clinical decisions historically had drawbacks. Until blood immunophenotyping standardization in the 1990s, results varied considerably across medical centers. Along with natural variation in CD4⁺ T cell counts across individuals and age groups, this contributed to diagnostic inconsistencies. Moreover, the decade-long lag between HIV-1 acquisition and the decline to very low levels of CD4⁺ T cells in blood posed another major challenge to understanding AIDS epidemiology and the link to HIV-1. Finally, antiretroviral therapy was initially indicated only once blood CD4⁺ T cell counts declined, as the virus was considered dormant until then (MILESTONE 16, 21).

This view was overturned by reports of acute CD4⁺ T cell depletion in the gut. In fact, activated memory CD4⁺ T cells, which are particularly permissive to HIV-1 replication and abundant in the intestine, are destroyed within days of infection in all tissues and in the circulation (MILESTONE 11). Loss of memory CD4⁺ T cells impairs replenishment of the mature T cell pool, thus contributing to systemic CD4⁺ T cell depletion (MILESTONE 13).

These studies illustrate the importance of research into viral entry receptors. CD4 opens the door to HIV-1, but it has also unlocked insights leading to disease control and prevention (MILESTONE 9, 20, 21).