Viral Characteristics Associated with the Clinical Nonprogressor Phenotype Are Inherited by Viruses from a Cluster of HIV-1 Elite Controllers

Abstract

A small group of HIV-1-infected individuals, called long-term nonprogressors (LTNPs), and in particular a subgroup of LTNPs, elite controllers (LTNP-ECs), display permanent control of viral replication and lack of clinical progression. This control is the result of a complex interaction of host, immune, and viral factors. We identified, by phylogenetic analysis, a cluster of LTNP-ECs infected with very similar low-replication HIV-1 viruses, suggesting the contribution of common viral features to the clinical LTNP-EC phenotype. HIV-1 envelope (Env) glycoprotein mediates signaling and promotes HIV-1 fusion, entry, and infection, being a key factor of viral fitness in vitro, cytopathicity, and infection progression in vivo. Therefore, we isolated full-length env genes from viruses of these patients and from chronically infected control individuals. Functional characterization of the initial events of the viral infection showed that Envs from the LTNP-ECs were ineffective in the binding to CD4 and in the key triggering of actin/tubulin-cytoskeleton modifications compared to Envs from chronic patients. The viral properties of the cluster viruses result in a defective viral fusion, entry, and infection, and these properties were inherited by every virus of the cluster. Therefore, inefficient HIV-1 Env functions and signaling defects may contribute to the low viral replication capacity and transmissibility of the cluster viruses, suggesting a direct role in the LTNP-EC phenotype of these individuals. These results highlight the important role of viral characteristics in the LTNP-EC clinical phenotype. These Env viral properties were common to all the cluster viruses and thus support the heritability of the viral characteristics.

Permanent control of HIV-1 pathogenesis in exceptional elite controllers: a model of spontaneous cure

“…These deleted genomes became dominant during follow-up 15 . In other studies, we could clone env sequences from EEC-3 in recombinant viruses that displayed a very limited and retarded replication capacity 40,41 , similarly to what has been observed in env recombinant viruses from some EC 42 . Pseudoviruses with env clones from EEC-3 exhibited a very low CD4 binding, transfer and fusion capacity, and a very inefficient cell signaling resulting in a very restricted replicative capacity 41 .…”

Evaluation of antiviral T cell responses and TSCM cells in volunteers enrolled in a phase I HIV-1 subtype C prophylactic vaccine trial in India

“…The risk of transmission is associated with high levels of viremia seen in acute and uncontrolled chronic infection. Though several studies have documented an inverse correlation between activated immune cells and viral load [3,38,39], their successful incorporation into vaccine design has not been achieved so far [37,40]. Adaptive T cell immunity provides the individual with a specialized defence against intracellular pathogens.…”

CD8+ T cells in HIV control, cure and prevention

“…Viral factors have also been implicated in modulating HIV control; however, it is difficult to distinguish causal from consequential associations due to CD8 + T cell-associated mutations that impair viral replication capacity 98 . Although it is clear that fully replication-competent viruses can be isolated from controllers 99 , control has also been associated with viruses harbouring mutations that impair viral replication fitness [100][101][102] events between controllers and progressors demonstrate that viral pro perties are neither necessary nor sufficient to mediate spontaneous HIV control 103,104 . Nonetheless, many transmitted viruses are pre-adapted to immune responses in their prior hosts, which may impair fitness and/or blunt the ability of CD8 + T cells to achieve spontaneous control in recipients expressing the same HLA allele 105,106 .…”