Toll-like receptors and HIV-1 disease progression: both direct and indirect roles?

Samuel O. Pine ^1,3, M. Juliana McElrath ^1,2,3, Pierre-Yves Bochud ^3,4

Special Author Introduction

The outcomes of HIV-1 infection are not homogenous across a population, instead comprising a spectrum of severity that depends in part on an individual's inherent ability to fight the virus.  Host genetic variation plays a crucial role in HIV-1 susceptibility, as exemplified by persons who possess two defective copies of the virus' co-receptor, CCR5, thus rendering them highly resistant to infection (1).  However, genetics also appear to matter in individuals already infected.  Much of this latter variation has been associated with the major histocompatibility genes (MHC), particularly the HLA-B gene locus.  Certain alleles of HLA-B allow the effective targeting of conserved HIV epitopes, which the virus appears unable to mutate without suffering a critical loss in viral fitness (2,3).  More recently, however, it has become evident that genetic variations in the innate immune system can affect the outcome of HIV-1 infection.

Although innate immune genes do not exhibit the inherent genetic diversity of the adaptive immune system, polymorphisms in toll-like receptors, or TLR, genes can lead to variable susceptibilities to a range of infections (4).  Single-nucleotide polymorphisms in TLR7, -8, -9, and now TLR4, have been associated with variable outcomes to HIV-1 infection, including rate of CD4⁺ T cell decline, time to AIDS-defining illness or CD4⁺ T-cell count threshold and time-to-death (5-7).  Our study reports that a tightly linked pair of TLR4 SNPs (D299G/T399I) is associated with higher viral loads early in infection, and that a non-coding TLR9 SNP previously reported to be associated with slow CD4+ T cell decline was was found less frequently among individuals with high viral setpoint.  It is intriguing that these associations involve TLR genes with no obvious direct mechanism for detecting HIV-1 virions.  While TLR7 and TLR8 (single-stranded RNA-sensing TLRs) activate innate immune pathways in the presence of HIV-1 virions or genomic RNA sequences, TLR4- and TLR9-dependent pathways are primarily activated by bacterial patterns (lipopolysaccharide (LPS) and unmethylated DNA patterns (CpGs) by TLR4 and TLR9, respectively).

It is possible that a connection exists between the association of TLR4 polymorphisms and the reported microbial translocation from the gut that occurs due to profound depletion of CD4⁺ cells in the gut mucosal tissues lining the intestine following HIV-1 infection (8).  Translocated LPS in the bloodstream of HIV-1-infected individuals may serve as an activating ligand for non-specific immune activation, and thus variations in LPS-sensing due to TLR4 polymorphisms could account for the association of TLR4 SNPs and higher peak viral load.  Alternatively, the TLR4 and TLR9 associations we observed could be related to a systemic regulation of colonized mucosal surfaces by TLRs (9,10).  In such a case, variations in TLR genes could be responsible for a higher overall activation state of mucosal surfaces, and would thus predispose certain individuals towards an acute HIV-1 infection that is characterized by higher levels of replicating virus.

Examining the role of innate immunogenetics in HIV-infected individuals may provide a better understanding of the multiple host-pathogen interactions involved in HIV infection, and may help establish new opportunities for interventions to improve HIV treatment.

Author Affiliations:

¹      Program in Pathobiology, Department of Global Health, and
²      Department of Lab Medicine, University of Washington
³      Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center
⁴      Infectious Disease Service and Institute of Microbiology, University Hospital and University of Lausanne, Switzerland 

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