Susceptibility to Repeated, Low-Dose, Rectal SHIV_SF162P3 Challenge Is Independent of TRIM5 Genotype in Rhesus Macaques

Abstract

Infections following repeated, low-dose (RLD), mucal S(H)IV exposures of macaques are used to model sexual HIV exposures for biomedical prevention testing. Different susceptibilities among animals can complicate study designs. In rhesus macaques, TRIM5 alleles Q, CypA, and TFP are resistance factors for infection with some S(H)IV strains, but not for SIV mac239 due to its capsid properties. SIV mac239 -derived SHIV SF162P3 has been demonstrated to reproducibly infect mucosally in vaginal and rectal RLD models. To further test the suitability of SHIV SF162P3 for RLD models, we studied the influence of the TRIM5 genotype on susceptibility to rectal RLD infection and on plasma viremia by analyzing 43 male Indian rhesus macaques from control arms of completed studies. The median number of exposures required for infection was three (Q/Q, n = 4) (TRIM5 alleles, number of macaques, respectively), four (Q/CypA, n = 7), three (TFP/Q, n = 15), three (TFP/TFP, n = 15), and two (TFP/ CypA, n = 2); TRIM5 CypA/CypA was not represented in our study. Median peak viremia (log 10 viral copies/ml) in infected animals was 7.4 (Q/Q, n = 4), 7.2 (Q/CypA, n = 6), 7.3 (TFP/Q, n = 13), 7.1 (TFP/TFP, n = 15), and 6.5 (TFP/ CypA; n = 2). Neither susceptibility nor peak viremia was significantly different (log rank test, Kruskal-Wallis test, respectively). Rhesus macaques' susceptibility to RLD SHIV SF162P3 is independent of the TRIM5 TFP, CypA, and Q alleles, with the limitation that the power to detect any impact of CypA/CypA and TFP/CypA genotypes was nonexistent or low, due to absence or infrequency, respectively. The finding that TRIM5 alleles do not restrict mucosal infection or ensuing replication rates suggests that SHIV SF162P3 is indeed suitable for RLD experimentation.

The metabolic and cardiovascular consequences of obesity in persons with HIV on long-term antiretroviral therapy

“…This was unexpected, and we postulate that adipocyte-derived IL-6 and TNF-α masked additional innate immune system activation due to HIV infection. Circulating hsCRP, IL-6, and TNF-α receptor 1 increased with total fat mass, and higher plasma levels of these biomarkers in obese HIV patients have been previously reported by our group and others [35, 36]. We postulate this finding reflects constitutive cytokine production by hypertrophied adipocytes and adipose-resident immune cells (primarily macrophages and, to a lesser extent, lymphocytes) as reported from in vitro studies [37–40].…”

“…This suggests the lack of a detectable difference, when present, was not clearly due to inadequate power. The sample size was calculated to provide 90% power to detect an association between body composition and serum IL-6 levels (based on previously reported cytokine levels in a similar cohort) [35], and 80% power to detect a 37% difference in IL-6 levels between obese HIV-infected and –uninfected subjects. Second, the use of DEXA imaging provided less accurate quantification of visceral fat than CT or MRI.…”

Short Communication: Viremic Control Is Independent of Repeated Low-Dose SHIVSF162p3Exposures

“…5 Also, Butler et al examined the role of host restriction factor TRIM-5a/CypA in rectal SHIV SF162p3 infections and reported that the presence/absence of these alleles had no bearing on infection or viremic outcomes in rhesus macaques. 13 Our current data add to these findings to indicate the number of exposures required for infection using this virus does not affect peak plasma virus levels, further characterizing the rectal repeat low-dose model.…”

“…Macaque infections and real-time polymerase chain reaction (PCR) measurements of viral loads were previously described. 5,[12][13][14][15][16][17][18][19] Real-time PCR viral load measurements across all studies were consistent in the use of the same primer/probe sequences targeting the virus core's gag region. Virus exposures and blood collection occurred once or twice per week, depending on respective study designs.…”

Blocking HIV-1 Infection by Chromosomal Integrative Expression of Human CD4 on the Surface of Lactobacillus acidophilus ATCC 4356

“…This model system could be improved by increasing the infection rate after intrarectal challenge with HIV-1. This may require repeated inoculations (the so-called multiple low-dose challenge method) used in nonhuman primate models (28,29). Despite evidence of protection after intrarectal challenge, there was no apparent protective efficacy against vaginal challenge.…”