Limited CD4+ T cell proliferation leads to preservation of CD4+ T cell counts in SIV-infected sooty mangabeys

Abstract

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections result in chronic virus replication and progressive depletion of CD4þ T cells, leading to immunodeficiency and death. In contrast, 'natural hosts' of SIV experience persistent infection with high virus replication but no severe CD4þ T cell depletion, and remain AIDS-free. One important difference between pathogenic and non-pathogenic infections is the level of activation and proliferation of CD4þ T cells. We analysed the relationship between CD4þ T cell number and proliferation in HIV, pathogenic SIV in macaques, and non-pathogenic SIV in sooty mangabeys (SMs) and mandrills. We found that CD4þ T cell proliferation was negatively correlated with CD4þ T cell number, suggesting that animals respond to the loss of CD4þ T cells by increasing the proliferation of remaining cells. However, the level of proliferation seen in pathogenic infections (SIV in rhesus macaques and HIV) was much greater than in non-pathogenic infections (SMs and mandrills). We then used a modelling approach to understand how the host proliferative response to CD4þ T cell depletion may impact the outcome of infection. This modelling demonstrates that the rapid proliferation of CD4þ T cells in humans and macaques associated with low CD4þ T cell levels can act to 'fuel the fire' of infection by providing more proliferating cells for infection. Natural host species, on the other hand, have limited proliferation of CD4þ T cells at low CD4þ T cell levels, which allows them to restrict the number of proliferating cells susceptible to infection.

Increased Stability and Limited Proliferation of CD4 + Central Memory T Cells Differentiate Nonprogressive Simian Immunodeficiency Virus (SIV) Infection of Sooty Mangabeys from Progressive SIV Infection of Rhesus Macaques

“…As expected, both the fraction (33.97% Ϯ 2.64% versus 57.88% Ϯ 1.69%; P Ͻ 0.0001) (see ϩ T cells were significantly lower in SIV-infected than uninfected RMs. However, consistent with previous reports (9,32,34,35), the large majority of SIV-infected SMs maintained their fraction and number of CD4 ϩ T cells at levels similar to those found in uninfected animals (see Fig. S1C and S1D in the supplemental material).…”

“…These data thus suggest that in pathogenic SIV infection, increased proliferation of CD4 ϩ TCM cells fails to maintain the homeostasis of the overall CD4 ϩ T cell compartment. Of note, this finding lends support to a previously described model that a heightened level of CD4 ϩ T cell proliferation can result in decreased numbers of uninfected CD4 ϩ T cells (35). The situation is exactly the opposite in SIV-infected SMs, in which the fraction of CD4 ϩ Ki-67 ϩ TCM cells is not increased compared to that in uninfected animals and, in fact, correlates positively with the level of CD4 ϩ T cells.…”

“…The average duration of infection in the SIV-infected SMs was 12.0 Ϯ 0.5 years, as estimated by the date of the first SIV-positive test, while the average duration of infection for RMs was 0.8 Ϯ 0.1 years. A well-documented feature that distinguishes natural SIV infection of SMs from progressive infection of RMs is the sustained preservation of circulating CD4 ϩ T cell counts despite high levels of virus replication (9,32,34,35). To validate this feature in our study, we first compared the relative (fraction of CD3 ϩ T cells) and absolute (number of cells per mm 3 of blood) levels of CD4 ϩ T cells between SIV-infected and uninfected animals.…”

Short Communication: HIV+ Viremic Slow Progressors Maintain Low Regulatory T Cell Numbers in Rectal Mucosa but Exhibit High T Cell Activation

“…4 Additionally, low percentages of CD4 + Ki67 + cells have been linked to CD4 preservation in SM. 34 While activated and effector memory cells support high levels of virus replication, limited proliferation and CCR5 expression in central memory CD4…”

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS

“…Furthermore, in contrast to the massive immune depletion that occurs in the gastrointestinal (GI) tract of non-natural hosts of SIV or HIV infection, natural NHP SIV hosts maintain GI epithelial integrity and exhibit a lack of microbial translocation that may in part account for minimal systemic immune activation [33,34]. Limiting the pool and/or proliferative capacity of target cells may also play a role in disease resistance, as demonstrated by studies in sooty mangabeys in which SIV replication was shown to be restricted to primarily short-lived activated CD4+ T-cells, which likely contributes to the preservation of central memory CD4+ T-cells [35,36]. A population of double negative (CD4-CD8-) T-cells capable of producing Th1, Th2 and Th17 cytokines have also been identified in sooty mangabeys, and are thought to compensate for CD4+ T-cell helper functions in SIV-infected animals [37].…”