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

Abstract

Depletion of CD4(+) central memory T (TCM) cells dictates the tempo of progression to AIDS in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) both in the natural history of infection and in the context of vaccination. CD4(+) TCM cells of sooty mangabeys (SMs), a natural host for SIV in which infection is nonpathogenic, are less susceptible to SIV infection than CD4(+) TCM cells of RMs. Whether this relative protection from infection translates into increased stability of CD4(+) TCM cells in natural versus nonnatural hosts has not yet been determined. Here we compared, both cross-sectionally and longitudinally, the levels of CD4(+) TCM cells in a large cohort of SMs and RMs and the association between CD4(+) TCM levels and the main virologic and immunologic markers of disease progression. Consistent with their lower susceptibility to infection, CD4(+) TCM cells of SIV-infected SMs are lost with kinetics 20 times slower than those of SIV-infected RMs. Remarkably, the estimated length of time of SIV infection needed for CD4(+) TCM cells to fall to half of their initial levels is <16 months for RMs but >17 years for SMs. Furthermore, the fraction of proliferating CD4(+) TCM cells is significantly lower in SIV-infected SMs than in SIV-infected RMs, and the extent of CD4(+) TCM cell proliferation is associated positively with CD4(+) T cell levels in SIV-infected SMs but negatively with CD4(+) T cell levels in SIV-infected RMs. Collectively, these findings identify increased stability and maintenance of the prohomeostatic role of CD4(+) TCM cells as features distinguishing nonprogressive from progressive SIV infections and support the hypothesis of a direct mechanistic link between the loss of CD4(+) TCM cells and disease progression.

Importance: Comparison of the immunologic effects of simian immunodeficiency virus (SIV) infection on rhesus macaques (RMs), a species characterized by progression to AIDS, and natural host sooty mangabeys (SMs), a species which remains AIDS free, has become a useful tool for identifying mechanisms of human immunodeficiency virus (HIV) disease progression. One such distinguishing feature is that CD4(+) central memory T (TCM) cells in SIV-infected SMs are less infected than the same cells in RMs. Here we investigated whether lower levels of infection in SMs translate into a better-preserved CD4(+) TCM compartment. We found that the CD4(+) TCM compartment is significantly more stable in SIV-infected SMs. Likely to compensate for this cell loss, we also found that CD4(+) TCM cells increase their level of proliferation upon SIV infection in RMs but not in SMs, which mechanistically supports their preferential infectivity. Our study provides new insights into the importance of long-term maintenance of CD4(+) TCM homeostasis during HIV/SIV infection.

FIG 1

Maintenance of CD4⁺ central memory T cell levels in naturally SIV-infected SMs. (A) Representative plots of the flow cytometry gating strategy for measurement of CD4⁺ TCM and TEM cells levels by CD62L staining for an SIV-infected SM. (B and C) Frequencies (of CD4⁺ CD95⁺ cells) (B) and counts (C) of CD4⁺ TCM cells were quantified in the whole blood of uninfected (◻) and SIV-infected (◼) RMs (***, P < 0.001; ****, P < 0.0001 [determined by t tests]). (D) The percentages of CD4⁺ TCM cells (of CD4⁺ CD95⁺ cells) in whole blood were compared between age-matched uninfected (○) and SIV-infected (●) SMs. (E) Numbers of CD4⁺ TCM cells (cells/mm³) were measured in the same cohort of SMs (ns, P value was not significant, as determined by the Mann-Whitney U test).

FIG 2

CD4⁺ TCM cells have increased stability in naturally SIV-infected SMs compared to SIV-infected RMs. (A to D) The percentages (of CD4⁺ CD95⁺ cells) (A and B) and counts (cells/mm³) (C and D) of CD4⁺ TCM cells were compared between uninfected and SIV-infected RMs (A and C) and SMs (B and D) based on their length of SIV infection (years) (***, P < 0.001; ****, P < 0.0001; ns, P value was not significant [as determined by t test {A and C} or Mann-Whitney U test {B and D}]). (E) Scatter plots depicting the relationship between the fraction of CD4⁺ TCM cells and the duration of infection at the time of sampling for RMs and SMs in order to estimate a linear decay rate of central memory cells (P < 0.0001 for differences in slopes, as determined by ANCOVA).

FIG 3

SIV infection of RMs, but not of SMs, is associated with a significant increase in the level of proliferating CD4⁺ TCM cells. (A and B) The percentages (A) and numbers (B) of proliferating (Ki-67⁺) CD4⁺ TCM cells in uninfected (□) and SIV-infected (■) RMs were compared. (C and D) The levels of proliferating CD4⁺ TCM cells were compared between age-matched uninfected (○) and SIV-infected (●) SMs by both frequencies (C) and cell counts (D) (****, P < 0.0001; ns, not significant [determined by Mann-Whitney U tests]).

FIG 4

The level of central memory CD4⁺ T cells correlates with viral load and CD4⁺ T cell levels in SIV infection of RMs. Shown are the correlations between the percentages of CD4⁺ TCM cells (of CD4⁺ CD95⁺ cells) and the viral load (A and C) and the percentages of CD4⁺ T cells (of CD3⁺ T cells) (B and D) for SIV-infected RMs (■) (A and B) and naturally SIV-infected SMs (●) (C and D). All statistical analyses were performed by using Spearman rank correlation tests.

FIG 5

Increased levels of proliferating CD4⁺ TCM cells are unable to maintain CD4⁺ T cell levels in pathogenic SIV infection of RMs. The correlations between the percentages of CD4⁺ Ki-67⁺ TCM cells (of CD4⁺ TCM cells) and the percentages of CD4⁺ T cells (of CD3⁺ T cells) (A and D) and CD4⁺ T cell counts (B and E) are shown for SIV-infected RMs (■) (A and B) and naturally SIV-infected SMs (●) (D and E). The fractions of proliferating CD4⁺ TCM cells were positively correlated with the viral load for SIV-infected RMs (C) but not for naturally SIV-infected SMs (F). Viral load measurements were log transformed prior to graphically plotting them against frequencies of proliferating CD4⁺ TCM cells; linear regression was then used to model the line of best fit between the two variables. All statistical analyses were performed by using Spearman rank correlation tests.