Nonprogressive and progressive primate immunodeficiency lentivirus infections

Abstract

Natural hosts for simian immunodeficiency virus (SIV) can be, and are often naturally, infected with species-specific SIVs, but do not develop acquired immunodeficiency syndrome (AIDS). These natural hosts maintain high SIV viral loads, but avoid immunodeficiency. Elucidating the mechanisms that allow natural hosts to coexist with SIV without overt disease may provide crucial information for understanding AIDS pathogenesis. Over the past few years, several key features of natural SIV infections have been described in studies conducted predominantly in sooty mangabeys (SMs), African green monkeys (AGMs), and mandrills. Natural SIV hosts are able to avoid the chronic, generalized immune system activation that is associated with disease progression in HIV-infected individuals and are known to downmodulate the expression of the receptors for SIV. In this perspective we propose that a critical factor that differentiates nonprogressive from progressive HIV or SIV infection is the maintenance of T cell immune competence in the face of a virus that infects and kills CD4(+) T cells. Elucidation of the mechanisms underlying the preservation of immune function during and after the acute phase of natural SIV infection may lead to the design of novel preventive and therapeutic interventions for treatment of chronic HIV infection.

Figure 1. Frequencies of CCR5⁺CD4⁺ T cells in progressive and nonprogressive infections

Depletion of GI tract CCR5⁺ CD4⁺ T cells during the acute and chronic phases of HIV in humans (black line) and SIV in rhesus macaques (red line), sooty mangabeys (blue line), and African green monkeys (green line). Graphs are based upon published data. Neither African green monkeys nor sooty mangabeys (naturally infected animals that do not progress to AIDS) are as dramatically depleted of their initial GI tract CD4⁺ T cell populations during the acute phase of infection as SIV-infected rhesus macaques or HIV-infected humans. African green monkeys and sooty mangabeys have very low frequencies of CCR5⁺CD4⁺ T cells prior to infection, unlike humans and rhesus macaques. Moreover, progressive depletion of GI tract CCR5⁺CD4⁺ T cells does not seem to occur in SIV-infected sooty mangabeys and African green monkeys during the chronic phase of infection.

Figure 2. Uncoupling of Disease Progression from Virus Production

(Top) In an uninfected host, naïve CD4⁺ T cells mature into central memory (CCR7⁺CD62L⁺, markers not shown) CD4⁺ T cells which may be regarded as having self-renewing potential. (CCR7⁻CD62L⁻) effector memory CD4⁺ T cells and activated CD4⁺ T cells are more prone to activation induced cell death. (center) In an HIV or SIV-infected host that progresses to AIDS, the infection and death of central memory CD4⁺ T cells eventually depletes this important cellular source and results in disease progression to AIDS. The infection and death of effector memory and activated CD4⁺ T cells produces the bulk of virus but makes little impact on these cellular pools as they are nonetheless destined to die by AICD. (bottom) In non-progressive SIV infection of natural hosts, virus load is maintained by the infection of effector memory and activated CD4⁺ T cells. The resistance of the ⁺ central memory CD4⁺ T cells to infection, by co-receptor down-regulation, prevents their depletion thus ensuring immune competence and precludes disease progression. Please label in figure as “Uninfected, etc.” Top to bottom.