Dataset Information

Alveolar Macrophage Dysfunction and Increased PD-1 Expression During Chronic SIV Infection of Rhesus Macaques.

ABSTRACT: HIV infected individuals have been shown to be pre-disposed to pulmonary infections even while receiving anti-retroviral therapy. Alveolar macrophages (AMs) play a critical role in lung innate immunity, but contradictory results have been reported regarding their functionality following HIV infection. Here, using the SIV rhesus macaque model, we document the effect of SIV infection on the phenotypic and functional properties of AMs. Following infection with SIV_mac251, AMs in bronchoalveolar lavage (BAL) sampled over 2- to 20-weeks post-infection (wpi) were compared to those in BAL samples from naïve macaques. AM expression of proinflammatory cytokines TNF-?, IL-6, IL-1?, and chemokine RANTES drastically increased 2-wpi compared to AMs of naïve macaques (p < 0.0001 for all), but dropped significantly with progression to chronic infection. Phagocytic activity of AMs 2-and 4-wpi was elevated compared to AMs of naive animals (p = 0.0005, p = 0.0004, respectively) but significantly decreased by 12-wpi (p = 0.0022, p = 0.0019, respectively). By 20-wpi the ability of AMs from chronically infected animals to perform SIV-specific antibody-dependent phagocytosis (ADP) was also diminished (p = 0.028). Acute SIV infection was associated with increased Fc?RIII expression which subsequently declined with disease progression. Frequency of Fc?RIII⁺ AMs showed a strong trend toward correlation with SIV-specific ADP, and at 2-wpi Fc?RIII expression negatively correlated with viral load (r = -0.6819; p = 0.0013), suggesting a contribution to viremia control. Importantly, PD-1 was found to be expressed on AMs and showed a strong trend toward correlation with plasma viral load (r = 0.8266; p = 0.058), indicating that similar to over-expression on T-cells, PD-1 expression on AMs may also be associated with disease progression. Further, AMs predominantly expressed PD-L2, which remained consistent over the course of infection. PD-1 blockade enhanced SIV-specific ADP by AMs from chronic infection indicating that the PD-1/PD-L2 pathway may modulate functional activity of AMs at that stage. These findings provide new insight into the dynamics of SIV infection leading to AM dysfunction and alteration of pulmonary innate immunity. Our results suggest new pathways to exploit in developing therapies targeting pulmonary disease susceptibility in HIV-infected individuals.

SUBMITTER: Hunegnaw R

PROVIDER: S-EPMC6618664 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Alveolar Macrophage Dysfunction and Increased PD-1 Expression During Chronic SIV Infection of Rhesus Macaques.

Hunegnaw Ruth R Mushtaq Zuena Z Enyindah-Asonye Gospel G Hoang Tanya T Robert-Guroff Marjorie M

Frontiers in immunology 20190703

HIV infected individuals have been shown to be pre-disposed to pulmonary infections even while receiving anti-retroviral therapy. Alveolar macrophages (AMs) play a critical role in lung innate immunity, but contradictory results have been reported regarding their functionality following HIV infection. Here, using the SIV rhesus macaque model, we document the effect of SIV infection on the phenotypic and functional properties of AMs. Following infection with SIV<sub>mac251</sub>, AMs in bronchoal ...[more]

PMID: 31333668

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Project description:UnlabelledDepletion 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.ImportanceComparison 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.

Dataset Information

Alveolar Macrophage Dysfunction and Increased PD-1 Expression During Chronic SIV Infection of Rhesus Macaques.

Publications

Alveolar Macrophage Dysfunction and Increased PD-1 Expression During Chronic SIV Infection of Rhesus Macaques.

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