HIV infection causes a biphasic destruction of CD4 T cells. A massive loss of memory CD4 T cells mediated by direct viral infection occurs during the early acute stages, followed by slow, progressive loss of CD4 T cells mediated by numerous mechanisms during the chronic stage (33
). After this initial destruction during the acute phase is likely a homeostatically driven expansion of remaining memory CD4 T cells—an expansion that cannot replace antigen-specific responses lost during the acute phase. Given the critical role of preexisting memory CD4 T cells in generating secondary immune responses, the loss of these antigen-specific responses during acute infection sets the stage of onset of immunodeficiency. Our studies show that animals sustaining lower peak plasma VLs also exhibit lower levels of memory CD4 T cell loss. Thus, clinical observations that high peak plasma VLs are associated with more rapid progression in HIV-infected humans can be explained by the concomitant greater destruction of the CD4 memory compartment during the acute stage. In addition, our findings underscore the necessity for HIV vaccines to ameliorate the virus-mediated destruction occurring in the first 2–4 wk after infection.
We evaluated the ability of a systemic DNA-prime rAd boost vaccine regimen to induce adaptive immune responses that could alter disease progression. DNA priming was performed three times at 1-mo intervals, with the rAd boost 3 mo later. Challenge with SIV Mac251 was initiated 2 mo after the rAd immunization. As has been observed for this regimen in the SHIV challenge model (13
), vaccination was partially protective in that the viral dynamics were tempered, with peak plasma VLs in most animals being ~10-fold lower than sham-treated controls after SIV challenge. Although this reduction (from 107
viral copies/ml of blood) may seem inconsequential, it was in fact accompanied by a strong reduction in the number of CD4 memory T cells that were infected and destroyed. Indeed, vaccination has a dramatic impact on this compartment. Whereas sham-treated animals lost 50–80% of their memory CD4 T cells, vaccinated animals lost only 5–20%, indicating that a large majority of preexisting CD4 memory responses were preserved by the vaccine regimen. Early preservation of these memory CD4 T cells has a significant impact on the outcome of disease course. Loss of fewer memory CD4 T cells was directly associated with better long-term survival.
Importantly, the systemic vaccination elicited mucosal T cell responses and, after challenge, provided protection against the catastrophic loss of CD4 T cells in the gut. The importance of this site to the pathogenesis of SIV/HIV has become clear in the last few years (1
). By far, the mucosa accounts for the greatest loss of CD4 T cells from the body. Thus, by preserving even 25% of the cells at this site, vaccination should dramatically improve mucosal immunity and health of the infected host.
Several factors could have played a role in the lower level of preservation observed in mucosal tissues, including the high dose of highly pathogenic SIVmac251, intravenous route of infection, and the disorganized nature of the effector mucosal compartment sampled in this study. Unlike the peripheral tissues, CD4 T cell targets are loosely distributed in the jejunal mucosa and could serve as readily available targets for the rapidly disseminating virus after intravenous challenge. These cells, once infected, are rapidly destroyed either by preexisting immune responses or virally mediated lysis. It is possible that a low dose of challenge by the mucosal route may lead to higher levels of memory CD4 T cell preservation in the mucosal tissues, as shown recently by Miller et al. (39
). Additionally, it is possible that mucosal immunization may generate better and stronger mucosal immune responses that could more effectively prevent the loss of mucosal CD4 T cells. Nonetheless, it is important to appreciate that even a 25% preservation of memory cells, compared with the near-total destruction in unvaccinated animals, could have significant long-term benefits for maintaining the integrity of the mucosal immune system, as has been demonstrated by Picker et al. (40
) These studies showed that animals that failed to repopulate mucosal tissues progressed faster compared with animals that partially repopulated the mucosal tissues.
Preservation of mucosal CD4 T cells has important implications for disease outcome and the onset of immunodeficiency. Mucosal tissues harbor most of the T cells in the body and are home to numerous pathogens. Loss of preexisting memory CD4 T cells severely compromises the ability of the mucosal immune system to maintain protective responses leading to the onset of numerous secondary infections. In addition, rapid infection and destruction of emerging HIV-specific CD4 T cell responses may severely compromise the generation and maintenance of subsequent HIV-specific CD8 T cell responses, leading to a failure to control viral infection. By maintaining the integrity of the mucosal immune system, vaccination can blunt the devastating effects of HIV and ensure better long-term outcome.
The vaccine induced both humoral and cellular immune responses. Although both have been implicated in the control of virus after challenge, the relatively small size of our study did not reveal a clear correlate of protection for either of these arms of the immune response. Nonetheless, our data suggest that the neutralization titres against the primary challenge isolate may associate with the control of peak plasma VL (and peak cell-associated VL). Notably, animal number 4934 had essentially undetectable neutralizing titres against primary SIVmac251 before challenge that did not boost by day 7 and sustained the highest VL amongst vaccinated animals—in the same range as the sham-treated animals. This animal had good neutralizing titres against the TCLA virus as well as systemic CD4- and CD8-specific responses. The T cell responses may have contributed to the eventual better control of viremia in this animal compared with sham-treated animals. These results are in concert with studies showing that administration of neutralizing antibodies attenuates pathogenicity in the SIV or SHIV models (6
). Furthermore, our results complement recent studies (42
) using CD8 depletion in SIVmac239Δ3-vaccinated macaques, suggesting that both neutralizing antibodies and CD8 T cells contribute to the containment of plasma viremia.
The generation of SIV/HIV-specific CD4 responses by a vaccine posed a conundrum; namely, although these responses are associated with better viral control by CD8 T cells, the cells provide a readily available substrate for viral replication. We found a similar level of preferential infection of SIV-specific CD4 cells in both vaccinated and unvaccinated animals as Douek et al. (11
) found for chronically HIV-infected humans. Using a vaccine that induced principally CD4 responses, Staprans et al. (12
) found that challenge led to exacerbated disease. In contrast, our vaccine regimen, which induces broad CD4, CD8, and humoral responses, resulted in a significantly tempered pathogenesis. Thus, we conclude that the trend toward preferential infection of vaccine-induced CD4 T cells does not bode poorly for infected subjects.
In summary, we demonstrate that cell-associated VLs and evaluation of memory CD4 T cell dynamics in multiple tissues serve as powerful correlates for measuring vaccine-induced protection. We show that a DNA-prime rAd boost vaccination dramatically reduces the level of infection and destruction of preexisting memory CD4 T cells during the early explosive phase of acute infection. Preservation of these cells will significantly aid in warding off immunodeficiency and the establishment of secondary infections. Finally, preservation of memory CD4 T cells was associated with better long-term outcome and survival. Thus, in the absence of sterilizing immunity, effective vaccination significantly blunts the destructive effects of early infection and plays an important role in maintaining the integrity of the immune system.