Rapid progression is associated with lymphoid follicle dysfunction in SIV-infected infant rhesus macaques.

HIV-infected infants are at an increased risk of progressing rapidly to AIDS in the first weeks of life. Here, we evaluated immunological and virological parameters in 25 SIV-infected infant rhesus macaques to understand the factors influencing a rapid disease outcome. Infant macaques were infected with SIVmac251 and monitored for 10 to 17 weeks post-infection. SIV-infected infants were divided into either typical (TypP) or rapid (RP) progressor groups based on levels of plasma anti-SIV antibody and viral load, with RP infants having low SIV-specific antibodies and high viral loads. Following SIV infection, 11 out of 25 infant macaques exhibited an RP phenotype. Interestingly, TypP had lower levels of total CD4 T cells, similar reductions in CD4/CD8 ratios and elevated activation of CD8 T cells, as measured by the levels of HLA-DR, compared to RP. Differences between the two groups were identified in other immune cell populations, including a failure to expand activated memory (CD21-CD27+) B cells in peripheral blood in RP infant macaques, as well as reduced levels of germinal center (GC) B cells and T follicular helper (Tfh) cells in spleens (4- and 10-weeks post-SIV). Reduced B cell proliferation in splenic germinal GCs was associated with increased SIV+ cell density and follicular type 1 interferon (IFN)-induced immune activation. Further analyses determined that at 2-weeks post SIV infection TypP infants exhibited elevated levels of the GC-inducing chemokine CXCL13 in plasma, as well as significantly lower levels of viral envelope diversity compared to RP infants. Our findings provide evidence that early viral and immunologic events following SIV infection contributes to impairment of B cells, Tfh cells and germinal center formation, ultimately impeding the development of SIV-specific antibody responses in rapidly progressing infant macaques.

SIV Infection Is Associated with Transient Acute-Phase Steatosis in Hepatocytes In Vivo.

Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a major cause of morbidity and mortality in HIV-infected individuals, even those receiving optimal antiretroviral therapy. Here, we utilized the SIV rhesus macaque model and advanced laparoscopic techniques for longitudinal collection of liver tissue to elucidate the timing of pathologic changes. The livers of both SIV-infected (N = 9) and SIV-naïve uninfected (N = 8) macaques were biopsied and evaluated at four time points (weeks -4, 2, 6, and 16-20 post-infection) and at necropsy (week 32). SIV DNA within the macaques' livers varied by over 4 logs at necropsy, and liver SIV DNA significantly correlated with SIV RNA in the plasma throughout the study. Acute phase liver pathology (2 weeks post-infection) was characterized by evidence for fat accumulation (microvesicular steatosis), a transient elevation in both AST and cholesterol levels within the serum, and increased hepatic expression of the PPARA gene associated with cholesterol metabolism and beta oxidation. By contrast, the chronic phase of the SIV infection (32 weeks post-infection) was associated with sinusoidal dilatation, while steatosis resolved and concentrations of AST and cholesterol remained similar to those in uninfected macaques. These findings suggest differential liver pathologies associated with the acute and chronic phases of infection and the possibility that therapeutic interventions targeting metabolic function may benefit liver health in people newly diagnosed with HIV.

Liver Bacterial Dysbiosis With Non-Tuberculosis Mycobacteria Occurs in SIV-Infected Macaques and Persists During Antiretroviral Therapy.

Liver disease is a significant contributor to morbidity and mortality in HIV-infected individuals, even during successful viral suppression with combination antiretroviral therapy (cART). Similar to HIV infection, SIV infection of rhesus macaques is associated with gut microbiome dysbiosis and microbial translocation that can be detected systemically in the blood. As microbes leaving the intestines must first pass through the liver via the portal vein, we evaluated the livers of both SIV-infected (SIV+) and SIV-infected cART treated (SIV+cART) rhesus macaques for evidence of microbial changes compared to uninfected macaques. Dysbiosis was observed in both the SIV+ and SIV+cART macaques, encompassing changes in the relative abundance of several genera, including a reduction in the levels of Lactobacillus and Staphylococcus. Most strikingly, we found an increase in the relative abundance and absolute quantity of bacteria within the Mycobacterium genus in both SIV+ and SIV+cART macaques. Multi-gene sequencing identified a species of atypical mycobacteria similar to the opportunistic pathogen M. smegmatis. Phosphatidyl inositol lipoarabinomannan (PILAM) (a glycolipid cell wall component found in atypical mycobacteria) stimulation in primary human hepatocytes resulted in an upregulation of inflammatory transcriptional responses, including an increase in the chemokines associated with neutrophil recruitment (CXCL1, CXCL5, and CXCL6). These studies provide key insights into SIV associated changes in hepatic microbial composition and indicate a link between microbial components and immune cell recruitment in SIV+ and SIV+cART treated macaques.