Abstract
BackgroundHIV infection causes a qualitative and quantitative loss of CD4+ T cell immunity. The institution of anti-retroviral therapy (ART) restores CD4+ T cell responses to many pathogens, but HIV-specific responses remain deficient. Similarly, therapeutic immunization with HIV antigens of chronically infected, ART treated subjects results in poor induction of HIV-specific CD4 responses. In this study, we used a macaque model of ART treatment during chronic infection to study the virologic consequences of SIV antigen stimulation in lymph nodes early after immunization. Rhesus CMV (RhCMV) seropositive, Mamu A*01 positive rhesus macaques were chronically infected with SIVmac251 and treated with ART. The immune and viral responses to SIV gag and RhCMV pp65 antigen immunization in draining lymph nodes and peripheral blood were analyzed. Animals were immunized on contralateral sides with SIV gag and RhCMV pp65 encoding plasmids, which allowed lymph nodes draining each antigen to be obtained at the same time from the same animal for direct comparison.ResultsWe observed that both SIV and RhCMV immunizations stimulated transient antigen-specific T cell responses in draining lymph nodes. The RhCMV-specific responses were potent and sustained (50 days post-immunization) in the periphery, while the SIV-specific responses were transient and extinguished quickly. The SIV antigen stimulation selectively induced transient SIV replication in draining lymph nodes.ConclusionsThe data are consistent with a model whereby viral replication in response to SIV antigen stimulation limits the generation of SIV antigen-specific responses and suggests a potential mechanism for the early loss and poor HIV-specific CD4+ T cell response observed in HIV-infected individuals.
Highlights
HIV infection causes a qualitative and quantitative loss of CD4+ T cell immunity
Two lymph nodes (LNs) biopsies draining either SIV gag or Rhesus CMV (RhCMV) pp65 injections from the same animal at the same time were obtained on the indicated days (D3: FH40 Inguinal; D5: DD05 Inguinal, D7: CT64 Inguinal; D9: FH40 Axillary; D11: DD05 Axillary, D14: CT64 Axillary) (Figure 1)
We found that the LN draining SIV gag on day 3, when the immune activation, as measured by IFN-g mRNA, was the highest, demonstrated potent gag-specific T cell responses based on IL-2, TNF-a and IFN-g production (Figure 3B and 3D)
Summary
HIV infection causes a qualitative and quantitative loss of CD4+ T cell immunity. The institution of anti-retroviral therapy (ART) restores CD4+ T cell responses to many pathogens, but HIV-specific responses remain deficient. Immunization of chronically infected, ART treated patients with HIV antigens does not result in the generation of significant HIV-specific CD4+ T cell responses, suggesting that HIV-specific CD4+ T cells are dysfunctional or preferentially depleted in infection and fail to recover [9,10,11]. In HIV-1 infection, lymphoid tissue represents an important site for viral replication, and the interaction between APC and CD4+ T cells may enhance viral replication by multiple mechanisms (reviewed in [13]). Given that HIV-specific CD4+ memory T cells are preferentially infected by HIV, carrying more viral DNA than total memory cells [18], we were interested in determining if activation of HIV-specific CD4+ T cells results in viral replication in lymphoid tissue
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