Antigen responsive CD4⁺T cell clones contribute to the HIV-1 latent reservoir

Abstract

<jats:title>Abstract</jats:title><jats:p>Antiretroviral therapy suppresses but does not cure HIV-1 infection due to the existence of a long-lived reservoir of latently infected cells. The reservoir has an estimated half-life of 44 months and is largely composed of clones of infected CD4<jats:sup>+</jats:sup> T cells. The long half-life appears to result in part from expansion and contraction of infected CD4<jats:sup>+</jats:sup> T cell clones. However, the mechanisms that govern this process are poorly understood. To determine whether the clones might result from, and be maintained by exposure to antigen, we measured responses of reservoir cells to a small subset of antigens from viruses that produce chronic or recurrent infections. Despite the limited panel of test antigens, clones of antigen responsive CD4<jats:sup>+</jats:sup> T cells containing defective or intact latent proviruses were found in 7 out of 8 individuals studied. Thus, chronic or repeated exposure to antigen may contribute to the longevity of the HIV-1 reservoir by stimulating the clonal expansion of latently infected CD4<jats:sup>+</jats:sup> T cells.</jats:p>

Single-cell TCR sequencing reveals phenotypically diverse clonally expanded cells harboring inducible HIV proviruses during ART

“…Altogether, these results indicate that T cell pools against specific antigens can comprise both infected and uninfected cells and suggest that reservoir cells from different individuals might be reactive to common antigens. This is in line with the results of recent studies demonstrating that at least a fraction of the HIV reservoir is carried by CMV/EBV and HIV-specific CD4+ T cells 23,[43][44][45] . In summary, our results indicate that antigen-driven clonal expansions highly contribute to the persistence of the translationcompetent HIV reservoir in individuals on ART.…”

“…During ART, clonally expanded HIV-infected cells have the ability to expand and contract over time 10,15,[19][20][21] . Several mechanisms are thought to contribute to the dynamics of the HIV reservoir 22 , including (1) antigen driven proliferation 23 , (2) homeostatic proliferation 4,24,25 , and (3) viral genome integration into specific cellular genes that may promote cell proliferation 6,8,9 . Altogether, these studies indicate that the reservoir is highly dynamic during ART but the relative contributions of these mechanisms remain unclear.…”

Antigen-driven clonal selection shapes the persistence of HIV-1 infected CD4+T cellsin vivo

“…These results provide strong evidence that CD4 + T cell clones carrying an inducible replication-competent provirus can be selected over time in response to a CMV. However, the size of infectious proviral clones within antigen-specific populations varied, as in the study from Mendoza et al (38). In participant P2, cells responding to anti-CD3/CD28 and CMVnonresponding cells had a significantly higher frequency of cells carrying inducible, replicationcompetent proviruses (18.3 and 33.5 IUPM, respectively, versus 2.7 IUPM in CMV-responding cells).…”

“…Thus, a better understanding of the mechanisms of HIV-1 persistence is needed. Two recent studies investigated the immunological factors contributing to the proliferation of the HIV-1 reservoir: Mendoza et al characterized proviral sequences from cells reactive to viral antigens (38), while Gantner et al profiled TCRβ sequences from cells with inducible p24 expression (59). Here, by combining provirus, integration site and TCRβ analyses from persistent clones with known specificities, we provide new insights into the importance of antigen-driven proliferation, relative to other drivers of clonal expansion, such as integration site effects and homeostatic proliferation.…”

“…However, it is unclear whether enrichment of HIV-1-DNA in certain antigenspecific cells is due to higher susceptibility to HIV-1 infection (36) or higher proliferation of infected cells driven by recurrent antigenic exposure (37). Recently, Mendoza et al showed that CD4 + T cell clones containing either defective or intact proviruses are present among CD4 + T cells responsive to chronic viral antigens (38). To provide definitive evidence for antigen-driven clonal expansion in vivo and assess its contribution to HIV-1 persistence relative to integration site driven proliferation, we studied the adaptive CD4 + T cell responses to CMV and HIV-1 Gag in individuals on ART.…”