Although most HIV controllers maintain strong HIV-specific T cell responses and extremely low levels of virus replication in the absence of therapy, no controller has ever eradicated HIV. We hypothesized that HIV-specific CD4+ T cells, although potentially supporting an effective HIV-specific immune response, might also serve as major target cells for HIV, continually replenishing the reservoir of latently infected cells. Supporting this hypothesis, we found that HIV controllers with the highest frequencies of activated and HIV-specific CD4+ T cells had the highest cell-associated burdens of HIV. Although higher viral burden could also be a cause of greater activated and HIV-specific CD4+ T cell expansion, we observed no evidence of a relationship between the degree of low-level viremia and the frequency of these cells. Furthermore, we found no evidence of a relationship between the cell-associated viral burden and HIV-specific CD8+ T cell frequencies. Collectively, these data support a model in which HIV-specific CD4+ T cells may replenish the latent reservoir and prevent the natural eradication of HIV infection in HIV controllers.
Our results are consistent with a recent report demonstrating that CD4+
T cells from HIV controllers are just as easily infected with HIV after ex vivo stimulation as cells from HIV-uninfected individuals [29
]. Although viruses from HIV controllers may be somewhat less fit than viruses from viremic individuals [30
], replication-competent virus can be isolated from many controllers and some have been infected with highly pathogenic viruses from individuals with AIDS [32
]. Despite infection with replication-competent viruses and having susceptible CD4+
T cells, HIV controllers maintain much lower cell-associated DNA levels than do HIV-infected individuals maintaining treatment-mediated viral suppression [17
]. These exceptionally small cellular reservoirs in HIV controllers have been largely attributed to a highly potent cytotoxic HIV-specific CD8+
T cell response, observable in the majority of these individuals [1
]. Enrichment for certain HLA and KIR allotypes in HIV controllers has also implicated a potential role of natural killer cells in clearing virally infected cells [35
]. Despite these potent cytotoxic antiviral responses, HIV controllers never completely eradicate HIV. Our results are consistent with the hypothesis that the very HIV-specific CD4+
T cell response coordinating an effective antiviral immune response may be contributing to viral persistence in this setting.
It has long been known that HIV-specific CD4+
T cells are more likely to be infected with HIV than non–HIV-specific CD4+
T cells [20
]. It is worth carefully considering this point in the context of HIV controllers because—as a group—they harbor extremely high frequencies of HIV-specific CD4+
T cells while maintaining extremely low proviral HIV DNA levels [3
]. Taken together, these observations might suggest that the latent reservoir in HIV controllers is more highly concentrated in the HIV-specific CD4+
T cell population than in most other HIV-infected individuals. This might be the case if HIV controllers were primarily containing viral replication in lymphoid tissues with high local concentrations of expanded HIV-specific T cells. If this hypothesis were true, it might have important implications for eradication strategies. For example, if reinfection of HIV-specific CD4+
T cells could be prevented in HIV controllers with combination antiretroviral therapy—preferably composed of agents targeting preintegration steps—repeated therapeutic vaccination with HIV antigens could potentially stimulate virus production by latently infected HIV-specific CD4+
T cells, allowing their clearance by the potent antiviral responses maintained by most of these individuals, potentially reducing the latent reservoir to low-enough levels that eradication might be possible. Although such a strategy would not have immediate relevance to the majority of HIV-infected individuals who fail to spontaneously control HIV replication, it might provide proof of principle that harnessing host anti-viral immune responses could play a role in HIV eradication.
The recognition that HIV-specific CD4+
T cells are likely to be major target cells for HIV even in controllers may also have relevance for T cell immunity vaccine strategies for HIV. Vaccines that elicit strong proliferative HIV-specific CD4+
T cell responses might actually increase the risk of HIV acquisition, as appeared to be the case in the recent STEP trial [14
]. Similarly, a therapeutic vaccine inducing a strong CD4+ T cell response actually shortened the time to viral rebound among HIV-infected individuals undergoing treatment interruption [36
], though this latter observation has not been observed with all therapeutic HIV vaccines [37
]. Indeed, low systemic immune activation levels have been consistently associated with a decreased risk of HIV acquisition in highly exposed HIV-uninfected individuals [38
], and blocking the recruitment of activated CD4+
T cell targets to mucosal surfaces with a topical microbicide appeared to protect macaques from systemic infection by the simian immunodeficiency virus following vaginal challenge [43
Our study has several limitations that deserve comment. First, our study is correlative, and we do not provide definitive proof that activated and HIV-specific CD4+
T cells are major contributors to viral persistence in HIV controllers. Indeed, higher cell-associated viral burden could be a cause rather than a consequence of the expansion of activated and HIV-specific CD4+
T cells observed. However, we found no evidence of an association between the extent of low-level viremia and the expansion of these cells. Furthermore, if higher viral burden was a major determinant of activated and HIV-specific T cell expansion in HIV controllers, we might have also expected to see strong and consistent associations between cell-associated viral burden and the frequency of HIV-specific CD8+
T cells. However, we saw, at best, inconsistent evidence of these relationships. The lack of consistent relationships between cell-associated viral burden and activated and HIV-specific CD8+
T cell responses might be explained by the countervailing antiviral activity of these cells. However, the contrasting relationships between cell-associated viral burden and HIV-specific CD4+
T cells further highlights the relative failure of HIV-specific CD4+
T cells to prevent viral persistence. Ultimately, isolating CD4+
T cells from blood and tissues and measuring HIV DNA levels separately within HIV-specific and non–HIV-specific fractions would be the most definitive way to assess whether the cellular viral burden in HIV controllers is preferentially maintained in the HIV-specific population [20
], but this is beyond the scope of the current study. Finally, not every HIV controller with high HIV-specific CD4+ T cell frequencies in our sample had high HIV DNA levels. In fact, the controller with the highest HIV-specific CD4+
T cell frequency had a very low HIV DNA level. Additional testing is necessary to address whether this individual has favorable CCR5 genetics or other important cellular restriction factors.
In summary, although most HIV controllers maintain high frequencies of potent HIV-specific T cells, none has ever successfully eradicated HIV. The strong relationship between the frequency of activated and HIV-specific CD4+ T cells and cell-associated viral burden in controllers may suggest that these cells are continually replenishing the latent reservoir, preventing the natural eradication of HIV in this setting. These observations have important implications both for the design of effective HIV vaccines and microbicides and for novel HIV eradication strategies.