Emergence of Simian Immunodeficiency Virus-Specific Cytotoxic CD4+ T Cells and Increased Humoral Responses Correlate with Control of Rebounding Viremia in CD8-Depleted Macaques Infected with Rev-Independent Live-Attenuated Simian Immunodeficiency Virus

Abstract

Indian rhesus macaques infected with the Rev-independent live-attenuated SIVmac239 strains control viremia to undetectable levels, have persistent but low cellular and humoral anti-SIV responses, and show no signs of immune deficiency. To analyze the immune mechanisms responsible for viral control, five macaques infected at day 1 after birth were subjected to CD8+ cell depletion at 6.7 y postinfection. This resulted in viremia increases to 3.7–5.5 log10 RNA copies, supporting a role of CD8-mediated responses in the control of viral replication. The rebounding viremia was rapidly controlled to levels below the threshold of detection, and occurred in the absence of SIV-specific CD8+ T cells and significant CD8+ T cell recovery in four of the five animals, suggesting that other mechanisms are involved in the immunological control of viremia. Monitoring immune responses at the time of viral control demonstrated a burst of circulating SIV-specific CD4+ T cells characterized as CD45RA−CD28+CD95+CCR7− and also granzyme B+, suggesting cytotoxic ability. Control of viremia was also concomitant with increases in humoral responses to Gag and Env, including a transient increase in neutralizing Abs against the neutralization-resistant SIVmac239 in four of five animals. These data demonstrate that a combination of cellular responses mediated by CD4+ T cells and humoral responses was associated with the rapid control of the rebounding viremia in macaques infected by the Rev-independent live-attenuated SIV, even in the absence of measurable SIV-specific CD8+ T cells in the blood, emphasizing the importance of different components of the immune response for full control of SIV infection.

CD4+T Cells Develop Antiretroviral Cytotoxic Activity in the Absence of Regulatory T Cells and CD8+T Cells

“…The inhibitory mechanism of CD8 ϩ T cells on CD4 ϩ T cell cytotoxicity is also not understood, but similar findings were made in CD8-depleted, simian immunodeficiency virus (SIV)-infected macaques, where GzmB-expressing CD4 ϩ T cells were shown to expand (51). One possible explanation is that CD8 ϩ Tregs might play a role.…”

Cooperativity of HIV-Specific Cytolytic CD4 T Cells and CD8 T Cells in Control of HIV Viremia

“…Subsequent analysis showed that this lack of control may be due to the depletion of cytolytic CD4 ϩ T cells. In contrast, depletion of CD8 ϩ T cells and control of SIV viremia was associated with the emergence of humoral and cytolytic CD4 ϩ T cell responses (23). Beyond natural HIV infection, the ability to degranulate upon antigenic recognition and release effector molecules such as perforin and granzyme B has been shown to be a key feature of antigen-specific CD4 ϩ T cells in other viral infections such as CMV and hepatitis C (26), as well as in cases of cancer (27) and after vaccination (2,28).…”

“…ϩ T cells exhibit a host of different helper functions that contribute to the HIV-specific immune response, a growing body of evidence supports the idea that direct cytolytic effector activity by CD4 ϩ T cells is also important for HIV control and clearance (1,23,24). Indeed, besides HIV-specific CD8 ϩ T cells, the emergence of HIV-specific cytolytic CD4 ϩ T cells during acute HIV infection has been linked to control of viral replication (5,25).…”

Cytotoxic CD4 T Cells—Friend or Foe during Viral Infection?

“…SIV-infected macaques controlling viral replication were depleted of CD8 T cells, leading to increased viremia that was rapidly controlled despite the lack of SIV-specific CD8 T cells (113). Viral control was associated with antibody responses and expansion of circulating SIV-specific CD4 T cells that were CD45RA− CD28+ CD95+ CCR7− and expressed GzmB (113).…”