Mechanisms and Factors That Drive Extensive Human Immunodeficiency Virus Type-1 Hypervariability: An Overview

Abstract

The extensive hypervariability of human immunodeficiency virus type-1 (HIV-1) populations represents a major barrier against the success of currently available antiretroviral therapy. Moreover, it is still the most important obstacle that faces the development of an effective preventive vaccine against this infectious virus. Indeed, several factors can drive such hypervariability within and between HIV-1 patients. These factors include: first, the very low fidelity nature of HIV-1 reverse transcriptase; second, the extremely high HIV-1 replication rate; and third, the high genomic recombination rate that the virus has. All these factors together with the APOBEC3 proteins family and the immune and antiviral drugs pressures drive the extensive hypervariability of HIV-1 populations. Studying these factors and the mechanisms that drive such hypervariability will provide valuable insights that may guide the development of effective therapeutic and preventive strategies against HIV-1 infection in the near future. To this end, in this review, we summarized recent advances in this area of HIV-1 research.

A-to-I editing of Malacoherpesviridae RNAs supports the antiviral role of ADAR1 in mollusks

“…Viral genomes rapidly diversify and evolve owing to a low replication fidelity, as referred for RNA viruses [37, 38], while the replication of DNA viruses is generally more accurate [39] and the evolvability of these viruses probably depend also on other mechanisms [40, 41]. Notably, an increased genetic variation can allow viruses to escape the host defenses [42, 43], but the accumulation of dysfunctional mutations in viral nucleic acids can be exploited as antiviral defense [44, 45]. Editing enzymes such as tRNA adenosine deaminases (ADAT), proteins of the activation induced cytidine deaminase (AID)/ apolipoprotein B editing complex (APOBEC) family and ADARs have been involved in the inactivation of RNA viruses and in the control of retroviruses or retrotransposons, among other processes such as carcinogenesis, diversification of antibodies and editing of various types of RNAs in mammals [46–48].…”

Public Immunity: Evolutionary Spandrels for Pathway-Amplifying Protective Antibodies

“…Hypervariable viruses such as HIV and influenza continue to defy conventional vaccine approaches (66)(67)(68)(69). Indeed, a major obstacle to eliciting broadly protective responses is largely attributed to the fact that the surface antigens of these viruses establish complex immunodominance hierarchies that effectively distract the host antibody response away from functionally conserved sites of vulnerability, both following infection or vaccination (62,(70)(71)(72)(73)(74)(75). It is well established that the strength of an antibody response against a given epitope is, in part, a function of the proportion and cognate affinities of the corresponding on-target BCRs present within the germline B cell repertoire (59,60,62,(76)(77)(78)(79)(80)(81)(82).…”

Harnessing Antibody-Dependent Cellular Cytotoxicity To Control HIV-1 Infection

“…Unfortunately, although the passive administration of bNAbs in both animal models and humans has resulted in viremia control, this control was temporary because of (i) the decline of antibody titers or (ii) the emergence of resistant mutants. The reason behind the emergence of resistant mutants is the high error-prone nature of this virus and the use of a single bNAb. To avoid such unwanted outcome, it has been suggested to use a combination of bNAbs .…”

“…133 Furthermore, targeting viral proteins (Nef and Vpu) or antagonizing their mediated functions is strongly suggested to control HIV-1 infection, at least, by means of enhancing ADCC responses. In addition, it is essential to realize that there are other important factors that can prevent the binding of ADCC-Abs to HIV-1 infected cells such as heavy glycosylation (glycan shield), 145 extreme hypervariability, 90 and limited number of HIV-1 glycoproteins on the surface of infected cells. 139 Latency.…”