Genetic and functional characterization of HIV-1 Vif on APOBEC3G degradation: First report of emergence of B/C recombinants from North India

Abstract

HIV-1 is characterized by high genetic heterogeneity which is a challenge for developing therapeutics. Therefore, it is necessary to understand the extent of genetic variations that HIV is undergoing in North India. The objective of this study was to determine the role of genetic and functional role of Vif on APOBEC3G degradation. Vif is an accessory protein involved in counteracting APOBEC3/F proteins. Genetic analysis of Vif variants revealed that Vif C variants were closely related to South African Vif C whereas Vif B variants and Vif B/C showed distinct geographic locations. This is the first report to show the emergence of Vif B/C in our population. The functional domains, motifs and phosphorylation sites were well conserved. Vif C variants differed in APOBEC3G degradation from Vif B variants. Vif B/C revealed similar levels of APOBEC3G degradation to Vif C confirming the presence of genetic determinants in C-terminal region. High genetic diversity was observed in Vif variants which may cause the emergence of more complex and divergent strains. These results reveal the genetic determinants of Vif in mediating APOBEC3G degradation and highlight the genetic information for the development of anti-viral drugs against HIV. Importance: Vif is an accessory HIV-1 protein which plays significant role in the degradation of human DNA-editing factor APOBEC3G, thereby impeding the antiretroviral activity of APOBEC3G. It is known that certain natural polymorphisms in Vif could degrade APOBEC3G relatively higher rate, suggesting its role in HIV-1 pathogenesis. This is the first report from North India showcasing genetic variations and novel polymorphisms in Vif gene. Subtype C is prevalent in India, but for the first time we observed putative B/C recombinants with a little high ability to degrade APOBEC3G indicating adaptation and evolving nature of virus in our population. Indian Vif C variants were able to degrade APOBEC3G well in comparison to Vif B variants. These genetic changes were most likely selected during adaptation of HIV to our population. These results elucidate that the genetic determinants of Vif and highlights the potential targets for therapeutics.

Immune escape mutations in HIV-1 controllers in the Brazilian Amazon region

“…Hassaïne [76] demonstrated that a tyrosine kinase (Hck) protein was able to inhibit the production and infectivity of a virus with mutant vif but not the wildtype virus, showing the role of certain mutations in the loss of protein efficacy. In an analysis of sequences from individuals from northern India, Ronsard [77] observed that mutations at positions 166 and 167 of vif affect viral infectivity, and Rousseau [66] associated a variant at position 33 with lower viral loads, suggesting a cost of mutation to viral fitness. Similarly, a case study in the United States investigated viral mapping of a mother and daughter (congenital transmission) who were slow progressors and identified a two-amino acid insertion in Vif that reduced the in vitro replication capacity of the virus in PBMCs by 20-fold.…”

Autophagy Intertwines with Different Diseases—Recent Strategies for Therapeutic Approaches

“…Critically, genetic variations in the viral genes like Tat and Vif result in differential viral activities, such as 1. varying levels of Tat interaction with the transactivation response RNA (TAR) element [139] and 2. Vif gene-induced differential APOBEC3 degradation [140], which results in a drastic increase of viral gene expression [141]. Among those, HIV-Tat plays a major role in regulating autophagy by affecting IFN-γ signaling through the suppression of STAT1 phosphorylation and consequently inhibiting major histocompatibility complex class-II antigen expressions.…”

Is the tryptophan codon of gene vif the Achilles’ heel of HIV-1?

“…The apolipoprotein mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3; A3) proteins are a family of seven cytidine deaminases (A3A, A3B, A3C, A3D, A3F, A3G, and A3H) that restrict certain lentiviruses, retrotransposons, hepatitis B virus and human papillomavirus [1][2][3][4]. Many studies focused on the genes A3F, A3G, and A3H because of their innate defense ability to restrict the replication of the HIV-1 [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. Particularly, A3F and A3G are incorporated into viral particles and during reverse transcription, within newly infected cells; by deamination, these proteins alter C in the viral minus-strand DNA to U.…”