Identification of a Cluster of HIV-1 Controllers Infected with Low Replicating Viruses

Abstract

Long term non-progressor patients (LTNPs) are characterized by the natural control of HIV-1 infection. This control is related to host genetic, immunological and virological factors. In this work, phylogenetic analysis of the proviral nucleotide sequences in env gene from a Spanish HIV-1 LTNPs cohort identified a cluster of 6 HIV-1 controllers infected with closely-related viruses. The patients of the cluster showed common clinical and epidemiological features: drug user practices, infection in the same city (Madrid, Spain) and at the same time (late 70’s-early 80’s). All cluster patients displayed distinct host alleles associated with HIV control. Analysis of the virus envelope nucleotide sequences showed ancestral characteristic, lack of evolution and presence of rare amino-acids. Biological characterization of recombinant viruses with the envelope proteins from the cluster viruses showed very low replicative capacity in TZMbl and U87-CD4/CCR5 cells. The lack of clinical progression in the viral cluster patients with distinct combinations of protective host genotypes, but infected by low replicating viruses, indicate the important role of the virus in the non-progressor phenotype in these patients.

Phenotypic characterisation of Human Immunodeficiency Virus type 1 Envelope entry efficiency of transmitted/founder variants circulating in Mbeya, Tanzania

“…However, the relationship between viral loads and entry efficiency lost significance at 12 mpi, suggesting that other factors, such as immune responses, could be influencing the association during later stages of infection. Overall, our results support the findings of Lassen et al, (2009) and Casado et al, (2013) who found that entry efficiency of viruses from seven ES and three LTNP, respectively were lower than those from chronic progressors, suggesting that viruses with poor entry could lead to viral control. In support, one of our PSV clones, 398, a LTNP with longitudinal viral loads below 2000 copies/ml (Casado et al, 2010) had the lowest entry efficiency.…”

“…Pseudovirions (PSVs) were generated to determine the effect of entry efficiency on viral load and to identify phenotypic properties that could influence this relationship. The only LTNP of this study had the lowest entry efficiency supporting the two previous studies that showed that viruses from HIV LTNP and ES had lower entry efficiency compared to chronic progressors (Lassen et al, 2009;Casado et al, 2013). We thus wanted to determine the impact of entry efficiency of T/F PSVs on viral loads from progressors subsequent to transmission.…”

“…However, most of these studies have focussed on Gag Cytotoxic T cell (CTL) escape mutations that attenuate viral replication, and no studies have investigated whether entry efficiency of T/Fs could also influence disease progression. However, Env also plays a major role in the competitive and adaptive ability of the virus (Rangel et al, 2003;Travers et al, 2005) and entry efficiency has been shown to be a determinant of overall viral fitness (Ball et al, 2003;Marozsan et al, 2005) and disease progression (Lassen et al, 2009;Casado et al, 2013). The influence of entry efficiency on disease progression has been limited to the study of long-term non-progressors (LTNP) and elite suppressors (ES) which showed that these individuals carried viruses in the chronic stage of infection with lower Env entry efficiency compared to progressors (Lassen et al, 2009;Casado et al, 2013).…”

“…However, Env also plays a major role in the competitive and adaptive ability of the virus (Rangel et al, 2003;Travers et al, 2005) and entry efficiency has been shown to be a determinant of overall viral fitness (Ball et al, 2003;Marozsan et al, 2005) and disease progression (Lassen et al, 2009;Casado et al, 2013). The influence of entry efficiency on disease progression has been limited to the study of long-term non-progressors (LTNP) and elite suppressors (ES) which showed that these individuals carried viruses in the chronic stage of infection with lower Env entry efficiency compared to progressors (Lassen et al, 2009;Casado et al, 2013). Furthermore, while there have been several studies characterizing the properties of transmitted viruses (Ochsenbauer et al, 2012;Ping et al, 2013;, there is limited information on the association between Env phenotypic properties of T/F variants and disease progression.…”

Factors Leading to the Loss of Natural Elite Control of HIV-1 Infection

“…Intrasample diversity was estimated by the best-fit model of nucleotide substitution in the MEGA 6 program. An estimation of viral infection time or "viral dating" was deduced, assuming a relaxed molecular clock, from the genetic distance of the nucleotide sequence of each subject virus to the MRCA (most recent common ancestor) of the HIV-1 Spanish epidemic (6,10,11,66).…”