Association Between HLA Gene Polymorphism And The Genetic Susceptibility Of HIV Infection

Human leukocyte antigen (HLA) complex, which refers to a group of closely linked genes on the short arm of the sixth human chromosome, is considered the most polymorphic genetic marker that has so far been reported in the human. HLA plays a significant role in the immune response, particularly in antiviral immunity. Although HLA and genetic predisposition to various autoimmune diseases have been separately studied for the past 40 years, the evaluation of the correlation between the two was initiated only within the last 10 years. In recent years, research on HLA polymorphisms and susceptibility to various infectious diseases has attracted significant attention owing to the critical role of HLA in diseases such as SARS and hepatitis B. In particular, HLA polymorphism, HIV, and genetic predisposition to AIDS have emerged as research areas of immense clinical significance.


Introduction
Human leukocyte antigen (HLA) complex, which refers to a group of closely linked genes on the short arm of the sixth human chromosome, is considered the most polymorphic genetic marker that has so far been reported in the human. HLA plays a significant role in the immune response, particularly in antiviral immunity. Although HLA and genetic predisposition to various autoimmune diseases have been separately studied for the past 40 years, the evaluation of the correlation between the two was initiated only within the last 10 years. In recent years, research on HLA polymorphisms and susceptibility to various infectious diseases has attracted significant attention owing to the critical role of HLA in diseases such as SARS and hepatitis B. In particular, HLA polymorphism, HIV, and genetic predisposition to AIDS have emerged as research areas of immense clinical significance.
Human immunodeficiency virus (HIV) infection is able to perturb and alter gene expression through several mechanisms that can, lastly, cause acquired immunodeficiency syndrome (AIDS) Figure 1. Meanwhile, associations between disease parameters and the genetic makeup of the host and virus may be crucial in determining the outcome of HIV-1 infection.
According to Joint United Nations Programme on HIV/AIDS, there were approximately 40 million HIV-infected people worldwide at the end of 2004. Limiting the susceptibility to HIV, predicting the course of AIDS, and reversing it are some of the challenging tasks that need to be addressed urgently. Existing data demonstrates that the susceptibility to HIV differs among individuals, and significant differences exist in the disease progression in HIV-infected persons. In general, it takes less than 10 years from the time of HIV infection to the manifestation of typical AIDS symptoms. However, a small subset of HIV-infected people (0.8%) are asymptomatic for over 10 years. According to a number of studies, the HLA complex is considered as the most noteworthy genetic marker that is closely related to AIDS progression and highlights the differences in genetic susceptibility of HIV-infected individuals.  and HLA-B*35 in ethnic groups of Han. However, findings of research on Caucasian individuals did not agree with this notion. HLA-B*07, found among people of African descent, is considered to correlate with the susceptibility to HIV, but the similar correlation has not been reported among people of other ethnic groups. Research on other ethnic groups indicates that HLA-B*18 and the HLA-A2 either influence HIV-1 infectivity or act as protective genes that inhibit the incidence of AIDS. The homozygous HLA-G 14-bp nsertion/deletion genotype is associated with higher viral load, lower CD4 cell count, and increased mortality compared with HLA-G 14-bp carriers.  Table 1.

HLA polymorphism and genetic predisposition to HIV
Richard et al characterized the differential cell surface expression levels of all common HLA-C allotypes and tested directly for effects of HLA-C expression on outcomes of HIV infection in 5243 individuals. They found that HIV peptides presented by higher expressed HLA-C alleles were more likely to elicit CTL responses than peptides presented by low expression HLA-C allotypes, such that higher HLA-C expression was correlated with increased likelihood of cytotoxic T lymphocyte responses and frequency of viral escape mutation. It is also pointed out that HLA-C and HLA-E collaborate to keep the HIV-1 virus at bay. HLA-C can present antigens to CTL, and it is able to inhibit NK cell lysis, but for some reason it is normally expressed on the cell surface at levels approximately 10-fold less than most HLA-A and HLA-B allotypes. The mechanisms that regulate HLA-C expression and the link between this molecule and HIV infection are not yet completely understood. Maybe a new miRNA targeting sequences identified on HLA-C gene and the low level of affinity between β2M and the HLA-C heavy chains can explain for this low level of expression.

3.
Statistical analysis of the correlation between HLA gene polymorphism and HIV infection or AIDS susceptibility: Previously published research findings have been analyzed to evaluate the diversity in the correlation of HLA with HIV/AIDS susceptibility. Metaanalysis was anticipated to identify the common features. Research articles that satisfy the selection criteria were retrieved and the original data in the documents were processed and analyzed, wherein B35, B62, DR5, and DR11 were identified as genes that facilitate HIV-1 susceptibility and/or occurrence of AIDS, while A10, B18, B27, B5, and DR1 were identified as protective genes against HIV-1 infection and/or occurrence of AIDS. Since meta-analysis is an observational study, variations are likely to be introduced in each step of the analysis, and the results need to be validated by testing in laboratories with a large sample size. chemotactic factors (CCR35 and CXCR4) are coreceptors for HIV-1. When HIV-1 infects target cells, the viruses that combine with CD4 molecules combine with coreceptors in order to enter the target cells. In high-risk populations with close contact to infected individuals but no infection, approximately one-third of the CCR5 alleles undergo deletion mutation; for instance, deletion of 32 bases of CCR5 genes (referred to as CCR5Δ32 mutation), which results in a natural immunity of the organism against HIV-1 infection at the gene level. The mutation and polymorphism changes of alleles not only influence the ability of HIV-1 to infect the target cells, but also change the onset and progression of AIDS. It is possible that HLA participates in HIV invading process through similar means, and affects AIDS progression. However, there are no validated reports on HLA's direct participation in HIV-1 infection by acting as the receptor, so far. Therefore, the susceptibility theory, which suggests that HLA acts as a receptor, needs to be subjected to further scientific scrutiny.

2.
HLA molecules selection pressure: The antigen-binding groove of HLA molecules combine with a specific epitope of the HIV protein (For example, gap 120), inducing the generation of helper T cells and cytotoxic T cells. In particular, CD8+ cytotoxic T lymphocytes can kill infected CD4 + T lymphocyte in a direct manner, which can influence virus replication, transmission, and AIDS progression. HLA molecules can employ different epitopes for the same molecule, and stimulate generation of CTLs featuring different quantities as well as specific properties, which has been confirmed in previous studies. Therefore, this can better explain the differences in AIDS progress when individuals with certain HLA phenotypes infected with HIV.
During viral infection, some viruses undergo degradation by cellular proteasome complex, and the cytosolic antigenic peptides are carried into the ER. In this organelle, the peptides are captured by HLA I molecules and then exposed on the cell surface, triggering the cytotoxic activity of the circulating CD8+ T lymphocytes, as described previously. The HIV has devised different ways to evade the immune response including a Nef-dependent mechanism that downregulates the HLA I expression, thus avoiding the recognition of the infected cells by CD8+ T lymphocytes (Fig2). Selectively, Nef alters the expression of HLA-A and -B by recognition of a sequence (Y320SQAASS) present on the cytoplasmic tail of these HLA molecules accelerating their endocytosis from the plasma membrane and blocking the transport of newly synthesized MHC class I molecules to the cell surface. Nef maintains the expression of HLA-C -G and -E unchanged, in order to inhibit the innate response of the natural killer cells (NK). Furthermore, the gp41 protein of the viral envelope upregulates the synthesis of IL-10 by monocytes; in turn, as mentioned before, this cytokine increases the expression of HLA-G molecules to control immune response and facilitate infection.
Meanwhile, under the influence of CTLs that are induced by HLA, mutation of HIV can occur. For example, TW10 peptide fragment (TAILQEQIAW) of gap protein in the HIV-1 virus, has a specific mutation on the residue 242 in the individuals with HLA-B57 or B58 and can revert to the wild type after the viruses detach from HLA-B57 or B58 molecules. This HIV mutation can cause functional loss of specific CTL, and enable HIV to adapt to the HLA environment and overcome the immune responses, resulting in HIV susceptibility of specific HLA types as well as a rapid progression of AIDS. Children of mothers with AIDS who have similar HLA genes are at a higher risk of being infected with HIV, and they tend to progress to AIDS in a shorter time. The possible reason for this is that the HIV of the mother might have adapted to the HLA environment in the host, and the virus replication increases when HLA similarity is high between the mother and child, which in turn makes it is easier for HIV to propagate and lead to a faster progression of AIDS. But sometimes specific mutation of HIV can also lead to a decrease in its virulence, enabling a reduced susceptibility of individuals towards HIV and a slower progression of AIDS.