Natural SIV hosts: showing AIDS the door

Abstract

Many species of African nonhuman primates are naturally infected with simian immunodeficiency viruses (SIVs) in the wild and in captivity. In contrast to HIV-infected humans, these natural SIV hosts typically do not develop AIDS, despite chronic infection with a highly replicating virus. In this Review, we discuss the most recent advances on the mechanisms of protection from disease progression in natural SIV hosts, with emphasis on how they differ from pathogenic HIV/SIV infections of humans and rhesus macaques. These mechanisms include: (i) resolution of immune activation after acute infection, (ii) restricted pattern of target cell infection, and (iii) protection from mother-to-infant transmission. We highlight the areas that should be pursued in future studies, focusing on potential applications for the treatment and prevention of HIV infection.

Figure 1. Mechanisms responsible for the low immune activation and lack of disease progression in SIV-infected natural hosts

The main immunological and virological features contributing to the lack of chronic immune activation and their key consequences resulting in protection from AIDS in natural SIV hosts are depicted.

Figure 2. Proposed mechanisms of target cell restriction in natural host species

(A) In pathogenic hosts such as RMs, activation of CD4+ T cells typically leads to robust surface expression of the HIV/SIV co-receptor CCR5, providing targets for infection and viral replication. Infection is distributed within both effector memory cells (Tem) and central memory cells (Tcm). Infection and disruption of the Tcm pool has been demonstrated to disrupt CD4+ T cell homeostasis in vivo (53). (B) Upon transition from naïve CD4+ T cells to memory cells, AGMs lower the surface expression of the CD4 molecule on a subset of CD3+CD4−CD8α^low lymphocytes that exhibit CD4+ T cell function and are infected by SIV at a lower frequency than naïve or memory CD4+ cells (58). AGMs also exhibit lower levels of CCR5 expression on CD4+ T cells than non-natural hosts (57). (C) Multiple, non-mutually exclusive mechanisms modulating SIV tropism have been described in SMs: (i) Upon activation, SM CD4+ Tcm cells maintain low levels of CCR5 relative to CD4+ Tem cells, resulting in significantly decreased levels of SIV infection (30); (ii) SMs have high levels of CD3+CD4−CD8− “double-negative” lymphocytes that exhibit T helper function, providing a potential surrogate for CD4+ T cells that is resistant to infection (60); (iii) Approximately 7% of captive SMs are homozygous for CCR5 mutations that abrogate surface expression, although these animals can be infected with SIV (59). Photo credit: S.E.B. and K.D. Mir.