Response to “The “gatekeeper” hypothesis challenged in a human cervico-vaginal tissue model for HIV-1 transmission”

“ Eppur si esiste (And yet it exists)”

To the Editor: The exclusive ability of HIV-1_R5 (not HIV-1_X4) to transmit infection in vivo suggests the existence of “gatekeeping” mechanisms that select one HIV variant over the other. In response to our paper,¹ which showed that human cervico-vaginal tissue ex vivo preferentially supports the productive infection of HIV-1_R5 rather than that of HIV-1_X4, Ariën et al.² report that cervico-vaginal migratory cells (MCs) are able to transfer equally both HIV-1_R5 and HIV-1_X4 to CD4-CCR5- and CD4-CXR4-transfected osteosarcoma cell lines and to activated peripheral blood mononuclear cells. Ariën et al. concluded that, “in contrast” with our results, their “findings suggest that both HIV-1_R5 and HIV-1_X4 can infect MCs and be transferred onto other HIV-1 target cells”.

We think that the results of our two groups are complementary rather than contradictory: the fact that HIV-1_R5 replicates more efficiently than HIV-1_X4 in cervico-vaginal tissue does not contradict the evidence that both infectious HIV-1_X4 and HIV-1_R5 virions can be retained by inoculated tissue in or on dendritic cells, macrophages, T-lymphocytes, or other cells and that such virus could be rescued from cervico-vaginal MCs (with phenotype and biological features yet to be defined) under appropriate experimental conditions. Moreover, quantitative rather than qualitative data on HIV-1_R5/HIV-1_X4 replication in MC co-cultures with indicator cells, as well as in cervico-vaginal tissues themselves, should be presented by Ariën et al. to conclude that HIV-1_R5 and HIV-1_X4 are transferred by MCs equally efficiently.

Recent reports^{3, 4} demonstrate that HIV-1 mucosal transmission requires a local expansion of a small founder population of infected cells in the cervico-vaginal mucosa in order to establish a systemic infection. Thus, a robust viral production in the genital tract rather than the simple retention and transfer of infectious particles appears to be critical for HIV-1 transmission. Therefore, in contrast to Ariën et al., we believe that our results indicate that one of the HIV-1_X4 gatekeeping mechanisms exist in the cervico-vaginal mucosa, preventing HIV-1_X4 from replicating as efficiently as HIV-1_R5.

Nevertheless, we agree with Ariën et al. that other mechanisms beyond the simple difference in coreceptor expression in cervico-vaginal cells are underlying gatekeeping: As we stated in our paper and elsewhere^{2, 5} and demonstrated for cervico-vaginal mucosa, there is no sole and exclusive impenetrable gatekeeper but rather multiple imperfect gatekeepers at different anatomical sites that collectively prevent HIV-1_X4 transmission via different routes.⁵ Future studies should identify the nature and decipher the molecular mechanisms of these gatekeeping barriers to develop new HIV-1 preventive strategies.