Compartmentalization and Clonal Amplification of HIV-1 Variants in the Cerebrospinal Fluid during Primary Infection

Abstract

Human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD) is a severe neurological disease that affects a subset of HIV-1-infected individuals. Increased compartmentalization has been reported between blood and cerebrospinal fluid (CSF) HIV-1 populations in subjects with HAD, but it is still not known when compartmentalization arises during the course of infection. To assess HIV-1 genetic compartmentalization early during infection, we compared HIV-1 populations in the peripheral blood and CSF in 11 primary infection subjects, with analysis of longitudinal samples over the first 18 months for a subset of subjects. We used heteroduplex tracking assays targeting the variable regions of env and single-genome amplification and sequence analysis of the full-length env gene to identify CSF-compartmentalized variants and to examine viral genotypes within the compartmentalized populations. For most subjects, HIV-1 populations were equilibrated between the blood and CSF compartments. However, compartmentalized HIV-1 populations were detected in the CSF of three primary infection subjects, and longitudinal analysis of one subject revealed that compartmentalization during primary HIV-1 infection was resolved. Clonal amplification of specific HIV-1 variants was identified in the CSF population of one primary infection subject. Our data show that compartmentalization can occur in the central nervous system (CNS) of subjects in primary HIV-1 infection in part through persistence of the putative transmitted parental variant or via viral genetic adaptation to the CNS environment. The presence of distinct HIV-1 populations in the CSF indicates that independent HIV-1 replication can occur in the CNS, even early after HIV-1 transmission.

Analysis of Dominant HIV Quasispecies Suggests Independent Viral Evolution Within Spinal Granulomas Coinfected with Mycobacterium tuberculosis and HIV-1 Subtype C

“…Third, longlived HIV lineages have previously been correlated with macrophage-targeting HIV variants in the CNS. 7,35 Finally, it is noteworthy that myeloid cells (macrophages, monocytes, and dendritic cells) have been shown to become infected with HIV following phagocytosis of infected T cells in the SIV model of infection. 38 A limitation of our study is the small sample size and the limited number of clones analyzed per compartment.…”

“…5 Following transmission, HIV-1 spreads to various anatomical sites where the site-specific microenvironment regulates its evolutionary kinetics. 6,7 HIV-1 replication in remote or sequestered anatomical sites may have clinical consequences by creating a source of virus for transmission, drug resistance (due to poor drug penetration), tissue-specific clinical deterioration, and establishment of long-lived viral reservoirs. 8,9 The role of coinfections such as TB, and related immune and cellular microenvironment remodeling in promoting independent viral evolution at tissue sites of infection, is poorly understood.…”

Cerebrospinal Fluid HIV Escape from Antiretroviral Therapy

“…In general, CSF viruses in early infection derive largely or exclusively from those in blood, presumably carried by and amplified within trafficking CD4+ T cells and monocytes; this has been termed non-compartmentalized or equilibrated CSF infection. Although CSF and plasma HIV sequences are almost identical in the early, noncompartmentalized infection, local clonal amplification can result in some population differences between CSF and blood [17][18][19]. These early CSF viruses generally use the CCR5 coreceptor and predominately infect CD4+ T cells (R5 and Ttropic viruses) [20••, 21, 22].…”

Plasmodium vivax Isolates from Cambodia and Thailand Show High Genetic Complexity and Distinct Patterns of P. vivax Multidrug Resistance Gene 1 (pvmdr1) Polymorphisms

“…8 The heteroduplex tracking assay (HTA) is a genotyping technique that has proven adept at uncovering minority variants within malaria infections and in infections with other agents. [13][14][15][16] Thus, it provides a more accurate picture of within-host genetic diversity. 17 It also facilitates the tracking of clones within hosts over time, potentially providing a nuanced portrait of relapsing vivax populations.…”