Research Article: Interplay between HIV-1 and Host Genetic Variation: A Snapshot into Its Impact on AIDS and Therapy Response

Date Published: May 16, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Raghavan Sampathkumar, Elnaz Shadabi, Ma Luo.


As of February 2012, 50 circulating recombinant forms (CRFs) have been reported for HIV-1 while one CRF for HIV-2. Also according to HIV sequence compendium 2011, the HIV sequence database is replete with 414,398 sequences. The fact that there are CRFs, which are an amalgamation of sequences derived from six or more subtypes (CRF27_cpx (cpx refers to complex) is a mosaic with sequences from 6 different subtypes besides an unclassified fragment), serves as a testimony to the continual divergent evolution of the virus with its approximate 1% per year rate of evolution, and this phenomena per se poses tremendous challenge for vaccine development against HIV/AIDS, a devastating disease that has killed 1.8 million patients in 2010. Here, we explore the interaction between HIV-1 and host genetic variation in the context of HIV/AIDS and antiretroviral therapy response.

Partial Text

The evidence for HIV to be the causative agent of AIDS was documented way back in 1983, and, hitherto, the dreadful HIV remains unconquered [1]. As of 2010, 34 million people are living with HIV infections and 2.7 million people have been newly infected in that year alone [2]. This alarming statistics have accelerated much research into the biology of HIV, seeking clues on “Achilles heel” so as to curtail its spread and eventually to eradicate it.

HIV-1 and HIV-2 cause AIDS, and HIV-1, with its tremendous diversity, outwits HIV-2 by its ability to inflict a more virulent form of the disease and has global distribution [3]. Both viruses originated in Africa, and viral zoonosis resulted in the rampant AIDS epidemic. Simian immunodeficiency virus (SIV) from chimpanzees (SIVCPZ) is closely related to HIV-1, while SIV from sooty mangabeys (SIVSM) forms the closest to HIV-2 [4, 5]. HIV-1 viruses fall under three main phylogenetic lineages, namely, M (Main), O (outlier), and N (non-M/non-O), all considered to have originated from chimpanzees dwelling in the eastern equatorial forests of Cameroon, West Central Africa, with O group viruses through a gorilla intermediate [6–8]. SIV infected Pan troglodytes troglodytes (Ptt) chimpanzees gave rise, through cross-species transmission, to HIV-1 groups M and N viruses while SIV-infected gorillas (Gorilla gorilla; SIVgor), which themselves contracted infection originally from chimpanzees, gave rise to formation of group O HIV-1 viruses. Recently, a variant of HIV-1 group O virus has been detected—P group—which resembles more closely to SIVgor than O group virus, in individuals of Cameroon origin [9, 10]. Studies have estimated the timing for origin of each lineage of HIV—HIV-1 group M, O, and N at 1931 (1915–1941), 1920 (1890–1940), and 1963 (1948–1977), respectively [11–13]. HIV-2 viruses are considered to have originated around 1930s [13].

HIV-1, with its RNA genome, demonstrates significant genetic diversity due its high mutation rate. It has diversified itself to such an extent, through its ability to form “cloud” of variants or quasispecies, that there is no single wild-type strain. In vitro data have shown that RNA viruses generate nonhomogeneous genetic clones that are closely related but genetically diverse, which are known as quasispecies. This phenomenon, which aids viruses to persist in their host, possibly causing disease, is observed in other RNA viruses such as hepatitis C and influenza virus as well [28, 29]. The reverse transcriptase (RT) of HIV-1, which lacks 3′-5′ exonucleolytic proof-reading function, misincorporates 1 in 6900 and 1 in 5900 nucleotides polymerized on the RNA and DNA template, respectively, and hence accounts for larger proportion of mutations seen in HIV-1 [30]. It has been estimated that, after a single round of HIV-1 replication, under the assumption of absence of selection pressure, the resulting progeny viruses will have substitution, frameshift and deletions at 24%, 4%, and 2%, respectively [31]. It is interesting to note that 80% of heterosexual-mediated HIV-1 infections are due to productive infection by a single HIV-1 virion [32–34]. HIV-1 evolves at about 1% per year [35]. Given that HIV-1 faces selection pressures, a gamut of mutations has shaped its genome since its origin, which in turn, ensures its virulence at population level [36, 37], despite the fact that certain mutations in its conserved region impacts its fitness negatively [38]. Further, a recent study that utilized phylogenetic comparative approach revealed that viral genotype, as against the host genetic profile, largely determines the HIV set-point viral load and hence the virulence [39]. A schematic sketch of error-causing machinery involved in HIV-1 mutagenesis and a gamut of selection pressure acting on HIV-1 are provided in Figures 3(a) and 3(b), respectively.

HIV-1 adapts to host immune pressure, and this is revealed through studies of positively selected amino acid changes in different proteins of the virus [70–74]. An immunoinformatic analysis that looked at envelope sequences across clades from varied geographical regions has indicated differences in frequency of positive selection (PS) sites, suggesting that viral clades prevalent in various geographically distinct parts of the globe evolve in response to the characteristic immunogenetic profile of the host population [70]. Evolutionary pathways of HIV-1 appear to be vast with occurrence of positive selection sites not only in epitopes of CD4+ and CD8+ T cells and antibodies, wherein HLA impacts profoundly, but also in other regions which are likely to suffer selection pressure via effectors of innate arm of the immune system such as KIR and HIV restriction factors TRIM5α, APOBEC3G [75]. In contrast, HIV-2 that causes less severe form of disease face significant negative selection pressure [76].

According to UNAIDS world AIDS day report 2011, at least 6.6 million people in low- and middle-income countries are receiving HIV treatment and this has resulted in prevention of 2.5 million AIDS deaths since 1995 [2]. Also ART prevents infection, as it reduces viral load and infectiousness of an infected individual [153]. While this is an encouraging sign towards combating the HIV/AIDS epidemic, it is to be emphasized that current drugs in the prescribed regimen are unable to attack and eradicate the viruses hiding in reservoirs such as seminal vesicles [154] and tissue macrophages of HIV infected patients [155]. Given the evidences that suggest continual on-going replication of HIV-1 in such reservoirs [156, 157], it is plausible that quasispecies that are immune to current combination ART drugs can emerge upon treatment interruption. HIV-1 occupies variety of anatomic compartments such as central nervous system (CNS), gut-associated lymphoid tissue (GALT), and genitourinary tract [158, 159]. The CNS, endowed with blood-brain-barrier, is a pharmacologically “privileged” site, and the virus inside CNS thus gets shielded from attack by some ART drugs [159–161]. Genotypic diversity of HIV-1 is not uniform across different compartments [162]. This can be inferred by the fact that majority variant seen in blood is not always so in semen [163, 164]. Further, env sequences from blood and male genital tract compartments differ [165]. Venturi et al. [166] have observed different drug resistance mutation profile between HIV-1 isolates from cerebrospinal fluid and plasma in patients under nonsuppressive ART drug regimens. Indeed selective drug pressure has been shown to result in multiple drug-resistant HIV-1 quasispecies [167]. Viral rebound in patients who cease to continue with the ART is an added concern [168].

The studies on biology of HIV-1 variation by characterizing emerging quasispecies population carries prognostic value as they impact rate of development of AIDS defining illnesses [187] as well as effectiveness of therapy [188]. Different recombinant forms of HIV-1 emerge, and they are seen to predominate in particular environments [189–191]. Given this scenario, more comprehensive epitope mapping studies with focus on CTL epitope escape mutants of CRFs, in addition to characterizing epitope profile of major HIV-1 clades, are warranted, and such findings will augment the efforts to curb spread of HIV-1, a virus nonpareil in medical history due to its ever elusive tricks inflicting damage to global health. The advent of HAART has made HIV/AIDS a life-threatening fatal into a potential chronic disease. However, HIV patients under long-term treatment are likely to have higher risk for medical complications like heart, liver, and neurodegenerative diseases, and hence there is an increasing need to deal with these additional health issues effectively [192]. A vaccine that could elicit sterilizing immunity against HIV/AIDS is much desired. Recent findings, RV144 Trial, with its finding that prime-boost vaccine combination of ALVAC-HIV and AIDSVAX® B/E offering 39.2% protection against HIV [193]; a 1% tenofovir gel inhibiting HIV sexual transmission by 39% [194]; a person with 12 years of infection considered to be cured of HIV as part of fighting acute myeloid leukemia via haematopoietic stem cell transplantation from a CCR5 ∆32 homozygous donor [195–197] are quite encouraging and serve as testimonial to the fact that HIV-1 can be conquered through further research which includes dissecting mechanisms of underlying protection and moving forward with those anti-HIV immunobiological clues [198–201]. While debate on attenuation of HIV-1, as it evolves continues [36, 37, 202, 203], focused and concerted efforts by scientists, employing multidisciplinary approaches to attack HIV, might enable achieving UNAIDS mission of “zero new HIV infections, zero discrimination and zero AIDS-related deaths” earlier.




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