Susceptibility to repeated, low-dose, rectal SHIVSF162P3 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 SIVmac239 due to its capsid properties. SIVmac239-derived SHIVSF162P3 has been demonstrated to reproducibly infect mucosally in vaginal and rectal RLD models. To further test the suitability of SHIVSF162P3 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 (log10 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 SHIVSF162P3 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 SHIVSF162P3 is indeed suitable for RLD experimentation.

FIG. 1.

TRIM5 genotypes versus susceptibility (number of SHIV_SF162P3 challenges until Infection). The number of exposures until infection was compared in 43 rhesus macaques of indicated Trim5 genotypes. There was no correlation between the genotype and the number of exposures with SHIV_SF162P3 that it took to infect (p=0.37, global log rank test). One week was subtracted for the eclipse phase when determining date of infection. The solid lines indicate the median number of SHIV exposures until infected. The open symbols represent the three uninfected animals in this study that had Q/CYPA (censored at 14 exposures) and TFP/Q (both were censored at 16 exposures) alleles.

FIG. 2.

TRIM5 genotype versus peak plasma viremia with SHIV_SF162P3. There was no association between the genotype and the amount of plasma viral RNA after infection with SHIV_SF162P3 (p=0.45; Kruskal–Wallis test). The solid lines indicate median RNA copies/ml.