Dynamics of HIV coreceptors and their utilization by plasma and cerebrospinal fluid HIV-1 isolates

Abstract: HIV-1 infection of CD4+ immune cells requires the assistance of cellular coreceptors. The regulation of these receptors is highly dynamic. In addition to the major coreceptors, CCR5 and CXCR4, several alternative coreceptors mediate entry for selected HIV isolates in vitro, although their role in vivo is yet to be established. Compartmentalized HIV-1 infection of the central nervous system (CNS) may cause neurological disease such as dementia. Several coreceptors that are distributed in the brain may mediate viral replication and contribute to neuropathogenesis. In early HIV infection virus phenotypes that use CCR5 (R5) predominate whereas the acquisition of CXCR4 use (X4 or R5X4) may occur during disease progression. In addition, R5 virus may develop altered CCR5 use in late stage infection. A CCR5 antagonist (Maraviroc) is now available for the treatment of R5 HIV-1 infection. We found that pro- and anti-inflammatory substances oppositely regulate monocyte expression of two HIV coreceptors, CCR2 and BLT1. The findings provide information about the regulation of monocyte trafficking during inflammatory conditions such as HIV-1 infection and further suggest that the dynamics of HIV coreceptor expression may be a target for pharmaceutical intervention. Investigating coreceptor use by paired plasma and cerebrospinal fluid (CSF) HIV-1 isolates we found a predominance of R5 phenotypes able to use CCR3 (R3R5) in CSF, also when X4/R5X4 virus dominated in plasma. R3R5 CSF variants correlated with late stage HIV-1 infection and high CSF viral load. CSF isolates from subtype C HIV-1 infected individuals generally used CXCR6, which also correlated with high viral load. The findings are relevant for the use of coreceptor antagonists to treat CNS HIV-1 infection and suggest that CCR3, a receptor expressed on brain target cells, may be important for HIV replication in the CNS. Furthermore, subtype specific differences in coreceptor use may remain unnoticed when analyzing plasma HIV-1 isolates. R5 plasma isolates from individuals in late stage HIV-1 infection displayed an altered use of CCR5, as determined by an increased ability to utilize chimeric CXCR4/CCR5 receptors. This correlated with a decreased basal sensitivity to in vitro inhibition by CCR5 antagonists TAK-779 and Maraviroc (MVC). V3 envelope polymorphisms, recently related to reduced virologic response to MVC in clinical trials, were displayed in some of the least susceptible isolates. The results provide theoretical support for an early initiation of CCR5 antagonists in HIV-1 infection.