Inhibition of HIV replication by CD8+ T cells correlates with CD4 counts and clinical stage of disease

Abstract

SUMMARY We sought to evaluate the relationship of CD8+ T cell‐mediated inhibition of autologous HIV replication in vitro to disease stage in HIV+ individuals. Depletion of CD8+ T cells from peripheral blood lymphocytes of 16 HIV+ subjects increased the percentage of virus‐producing cultures from 56% to 81%. CD4+ T cells were purified from 52 HIV+ individuals and cultured alone or in the presence of autologous CD8+ T cells. In 13 (25%) subjects HIV replication was only detected in the absence of CD8+ T cells (inhibition positive); in 26 (50%) viral replication occurred both in the absence and presence of CD8+ cells (inhibition negative). In the remaining 13 (25%) subjects, CD8+ T cell‐mediated inhibitory activity could not be evaluated because stimulation of their purified CD4+ T cells did not result in p24 production. In some virus culture‐negative individuals, the inability to demonstrate HIV replication was due to the presence of low numbers of CD8+ T cells that co‐purified with CD4+ T cells. Detection of inhibitory CD8+ T cells was associated with significantly higher CD4 counts and better clinical status compared with inhibition‐negative subjects. These results demonstrate that CD8+ T cell‐mediated inhibition of HIV replication correlates with disease stage, and thus may play a role in preventing disease progression. CD8+ T cells did not inhibit autologous HIV replication across a semipermeable membrane. Further, the ability of CD8+ T cells to prevent HIV replication did not correlate with lysis of autologous CD4+ T cells. Thus, CD8+ T cells inhibited autologous HIV replication in vitro through a contact mediated non‐lytic mechanism.

Natural Suppression of Human Immunodeficiency Virus Type 1 Replication Is Mediated by Transitional Memory CD8+T Cells

“…Importantly, the viremic individuals in this study were healthy long-term survivors of HIV infection and exhibited low viral loads (median, 3.9 logs) ( Table 1). Indeed, our findings are consistent with those of previous studies establishing this anti-HIV response as a characteristic of CD8 ϩ cells from asymptomatic long-term survivors with low-level viremia (3,7,14,25,35).…”

“…In previous studies, we observed that CD8 ϩ cells from HIVinfected individuals vary in their abilities to suppress HIV replication in primary CD4 ϩ cells; CD8 ϩ cells from asymptomatic persons have the highest CD8 ϩ cell noncytotoxic antiviral response (CNAR) (3,7,14,21,25,35,52). To further characterize this anti-HIV activity, we systematically compared the whole-blood frequencies (Table 1) and HIV-suppressing activities of various CD8 ϩ cell subsets ( Fig.…”

“…This CD8 ϩ cell noncytotoxic antiviral response (CNAR) becomes evident during the acute stage of infection (22,38), varies in magnitude among HIV-infected persons (21,35,52), and directly correlates with a healthy clinical state (3,6,7,14,25,35). Strong CNAR activity is a feature of long-term survivors (LTS) of HIV infection (3,14).…”

CD8+ Cell Anti-HIV Activity Rapidly Increases Upon Discontinuation of Early Antiretroviral Therapy

“…Distinct from their classical cytotoxic function, CD8+ cells can suppress HIV replication through noncytotoxic mechanisms [17,18,[21][22][23][24]. The CD8+ cell noncytotoxic anti-HIV response (CNAR) is particularly relevant because of its direct correlation with a healthy clinical state [25][26][27][28][29]. Asymptomatic long-term survivors of HIV infection have strong CNAR activity, whereas this response is lost with progression to disease [26][27][28][29][30][31][32].…”

“…The CD8+ cell noncytotoxic anti-HIV response (CNAR) is particularly relevant because of its direct correlation with a healthy clinical state [25][26][27][28][29]. Asymptomatic long-term survivors of HIV infection have strong CNAR activity, whereas this response is lost with progression to disease [26][27][28][29][30][31][32]. Additional features of CNAR include (1) its effectiveness on divergent strains and subtypes of HIV [22,28,33], (2) its specific effect of blocking LTR-driven transcription [34][35][36], and (3) its association with the secretion of the CD8+ cell antiviral factor (CAF) [18,[36][37][38].…”