Evidence for both Intermittent and Persistent Compartmentalization of HIV-1 in the Female Genital Tract

Abstract

HIV-1 has been shown to evolve independently in different anatomical compartments, but studies in the female genital tract have been inconclusive. Here, we examined evidence of compartmentalization using HIV-1 subtype C envelope (Env) glycoprotein genes (gp160) obtained from matched cervicovaginal lavage (CVL) and plasma samples over 2 to 3 years of infection. HIV-1 gp160 amplification from CVL was achieved for only 4 of 18 acutely infected women, and this was associated with the presence of proinflammatory cytokines and/or measurable viremia in the CVL. Maximum likelihood trees and divergence analyses showed that all four individuals had monophyletic compartment-specific clusters of CVL- and/or plasma-derived gp160 sequences at all or some time points. However, two participants (CAP177 and CAP217) had CVL gp160 diversity patterns that differed from those in plasma and showed restricted viral flow from the CVL. Statistical tests of compartmentalization revealed evidence of persistent compartment-specific gp160 evolution in CAP177, while in CAP217 this was intermittent. Lastly, we identified several Env sites that distinguished viruses in these two compartments; for CAP177, amino acid differences arose largely through positive selection, while insertions/deletions were more common in CAP217. In both cases these differences contributed to substantial charge changes spread across the Env. Our data indicate that, in some women, HIV-1 populations within the genital tract can have Env genetic features that differ from those of viruses in plasma, which could impact the sensitivity of viruses in the genital tract to vaginal microbicides and vaccine-elicited antibodies. IMPORTANCE Most HIV-1 infections in sub-Saharan Africa are acquired heterosexually through the genital mucosa. Understanding the properties of viruses replicating in the female genital tract, and whether these properties differ from those of more commonly studied viruses replicating in the blood, is therefore important. Using longitudinal CVL and plasma-derived sequences from four HIV-1 subtype C-infected women, we found fewer viral migrations from the genital tract to plasma than in the opposite direction, suggesting a mucosal sieve effect from the genital tract to the blood compartment. Evidence for both persistent and intermittent compartmentalization between the genital tract and plasma viruses during chronic infection was detected in two of four individuals, perhaps explaining previously conflicting findings. In cases where compartmentalization occurred, comparison of CVL- and plasma-derived HIV sequences indicated that distinct features of viral populations in the CVL may affect the efficacy of microbicides and vaccines designed to provide mucosal immunity.

Advancing HIV Vaccine Research With Low-Cost High-Performance Computing Infrastructure: An Alternative Approach for Resource-Limited Settings

“…These types of analyses include virus phylodynamics that provide insights into, for example, intra-host evolution of HIV-1 by estimating the rates of evolution, selection, diversity, divergence, elucidating spatio-temporal distributions of viruses, and identifying number of viral infections. 19 , 20 …”

“…These types of analyses include virus phylodynamics that provide insights into, for example, intra-host evolution of HIV-1 by estimating the rates of evolution, selection, diversity, divergence, elucidating spatio-temporal distributions of viruses, and identifying number of viral infections. 19,20 To achieve this, we installed a number of phylodynamics programs on the cluster, including Bayesian Evolutionary Analysis by Sampling Trees (BEAST), 21 which uses Bayesian statistical methods that require long computational times and memory requirements. BEAST ran faster on the bioinformatics cluster compared with an ordinary machine (164 and 284 hours, respectively) to complete the same task ( Table 1).…”

Quasispecies Composition of Small Ruminant Lentiviruses Found in Blood Leukocytes and Milk Epithelial Cells

“…A study on SRLVs compartmentalization performed to date revealed the presence of different viral sequences in the blood, mammary gland, lungs, and central nervous system tissue in clinically affected sheep [6] and in the colostrum and peripheral blood of goats [5,8]. Similarly, compartmentalization has been well documented in the brain, cerebrospinal fluid, and genital tract, as well as in the gut, lung, liver, kidney, and breast milk of patients infected with HIV-1 [34][35][36][37][38]. In the current study, SRLVs sequences from PBLs and milk epithelial cells were genetically similar suggesting an equilibrium of virus between these compartments.…”

HIV drug resistance in various body compartments

“…Rare cases have been reported of patients with detectable cervicovaginal lavage (CVL) viral loads despite suppression of blood plasma HIV [66] and partial compartmentalization with partial mixing of infected cells and viruses between the genital tract and the blood [12,[67][68][69]. A few reports found HIV drug resistance profiles in CVL and blood that were discordant [68][69][70].…”