HIV-1 Vpr: Genetic Diversity and Functional Features from the Perspective of Structure

Abstract

RNA viruses are well known for the enormous genetic variation. Retroviruses share this feature with other RNA viruses, and human immunodeficiency virus type 1 (HIV-1) has been extensively investigated in this regard. Based on the DNA sequence analysis, HIV-1 has been classified into three groups; M, N, and O, with viral subtypes in each group. While the genetic variation between viral isolates has been documented throughout the genome, specifically, the env gene exhibits high variation. Analysis of the env gene from the sequential samples from HIV-1-infected patients reveals variation in the range of 1% per year. The variation observed in individual HIV-1 genes in the form of changes at the nucleotide level, as expected, should result in one of the possible scenarios: (1) no change in the amino acid, (2) conservative change in the amino acid, (3) nonconservative change in the amino acid, and (4) premature stop codon resulting in a truncated protein. Hence, it is likely that the variation may impact on the function of the protein, depending on the nature of the mutation. The goal of this review is to summarize the polymorphisms in Vpr using the available sequence information and discuss their effects on the functions of Vpr from the point of view of its structure. The data generated by several groups provide a base for understanding the consequences of natural polymorphisms in specific regions of the Vpr molecule. However, it is also clear that secondary changes (second site or compensatory mutations) may modify the effect of a specific mutation and a comprehensive analysis is needed to delineate the role of specific residues in Vpr molecule. This is an area which, we hope, will attract investigators for further studies, and may provide information for understanding the molecular basis of Vpr functions.

The Role of Vpr in the Regulation of HIV-1 Gene Expression

“…23,24 The 14 kDa HIV-1 late accessory protein, Vpr, has received significant attention due to its regulatory effect upon virus and host functions. [25][26][27] At the cellular level, expression of Vpr results in deregulation of the cell cycle and accumulation of the cells at the G 2 /M stage of the cell cycle, [28][29][30] which may result in cell death. In addition, expression of Vpr can induce apoptosis through a variety of mechanisms.…”

Transmitted/Founder HIV-1 Subtype C Viruses Show Distinctive Signature Patterns in Vif, Vpr, and Vpu That Are Under Subsequent Immune Pressure During Early Infection

“…Therefore, it is plausible that in HIV-1 subtype C infection, two conserved arginine residues at positions 73 and 80 are sufficient for adenine nucleoside translocator interaction. 36 Other well-known substitutions, such as E21P, E24P, and A59P, which prevent the incorporation of Vpr into virus-like particles, as well as Q65R, which is correlated with impairment of Vpr docking at the nuclear envelope, 59 were not observed in this study. Neither were other known substitutions, underlying the integrity of Vpr during early HIV-1C infection.…”

A Mutagenesis Approach for the Study of the Structure-Function Relationship of Human Immunodeficiency Virus Type 1 (HIV-1) Vpr

“…Several other studies showed marked heterogeneity in vpr sequences derived from multiple patient samples Kuiken et al, 1996). In addition to length polymorphisms, numerous studies have demonstrated an association between substitution mutants in the amino acid sequence of Vpr and disease (Caly et al, 2008;Lum et al, 2003;Tungaturthi et al, 2004). Caly et al (2008) found a mutation, F72L, in several vpr sequences derived from a single patient with LTNP status.…”

“…After seroconversion to HIV-positive status, the viral loads measure at 10000-50000 viral RNA copies per ml of patient sera during the asymptomatic A Mutagenesis Approach for the Study of the Structure-Function Relationship of Human Immunodeficiency Virus Type 1 (HIV-1) Vpr 205 stage; in the later stages of disease, viral RNA genomes can increase to several million copies per ml (Poropatich and Sullivan, 2011;Tungaturthi et al, 2004). Thus, a high replication rate produces tremendous variation in the viral population within a single patient.…”

“…Extensive studies have shown that coactivation of glucocorticoid receptor by Vpr, resulting in transcription of elements in the promoter regions of the HIV LTR and host genes, enhances viral replication and downregulates host immune responses Hapgood and Tomasicchio, 2010). Vpr also drives apoptosis and G2 cell cycle arrest (Morellet et al, 2009;Pandey et al, 2009;Tungaturthi et al, 2004). The processes enhance immune escape and HIV-1 replication, respectively.…”