Genetic Determinants Of Hiv Infection

The term Human Immunodeficiency Virus is commonly known as (HIV), which is a virus that attacks the immune system of humans by destroying the amount of CD4 cells in their bodies. Without CD4 the human body is unable to fight against diseases, which can lead to Acquired Immune deficiency syndrome known as AIDS for short. The first case of the HIV/AIDS virus in the U.S. occurred in the early 1980’s. The first spark of the virus was found in San Francisco with couple of homosexual Caucasian American males. Today African Americans account for the largest proportion of HIV and AIDS in this country, represent approximately 13% of the U.S. population, but accounted for an estimated 44% of new HIV infections in 2010(the last year a study was

(2011) was a multi-continent, randomized, controlled trial to evaluate the effectiveness of antiretroviral therapy on the speed of the disease process among HIV-1 infected and HIV-1 uninfected partners. In the study, 1,763 HIV mixed status couples were grouped into either early antiretroviral and delayed therapy groups. Inclusion criteria consisted of the HIV-1 infected participant having a CD4 count between 350 and 550 with no previous antiretroviral therapy usage, except to prevent mother-baby transmission. Participants attended three monthly sessions and then quarterly sessions until ill or requiring an additional amount of antiretroviral drugs (Cohen et al, 2011). The uninfected partners were tested each quarter for seroconversion, the period in time in which antibodies become detectable. The research study concluded that early antiretroviral therapy initiation had a greater effect on CD4 count than delayed antiretroviral therapy. The average CD4 count in the early therapy group originated at 400 and increased to 603 after 12 months of ART. A decline of CD4 cells were noted in the delayed group (Cohen et al, 2011). The authors concluded that a higher incidence of HIV transmission was noted in African countries and adverse effects were more likely to occur in the early therapy group. Early therapy had a positive effect on the HIV-1 uninfected and HIV-1 infected

Recent studies suggested that CD4 domain specific monoclonal antibody such as mAb (15A7) and Ibalizumab have a great revolution in HIV-1 treatment area. The majority of previous mentioned treatments constitute to either restore the immune response or decline the plasma vireamia, however, this type of treatment is more likely to interfere with the HIV-1 structure. Before explaining how this category of drugs works, it is necessary to clarify the reaction between HIV-1 glycoproteins and CD4. Once the virus enters the body, HIV-1 envelope glycoprotein (gp120) attaches to a cellular CD4 receptor. As CD4/gp120 is formed, it allows gp120 to attache to chemokine receptor-5 (CCR5) or CX chemokine receptor-4 (CXCR4) allowing gp41, another viral envelope molecule, to insert into the target cell membrane leading to fusion the viral envelope and cellular membrane (Christopher et al., 2010). Ibalizumab is CD4 domain-2 monoclonal antibody using as an effective treatment to enhance the CD4 counts. In a study which set out to determine the antiviral efficacy of Ibalizumab on HIV-1 positive patients not on (ART), (Christopher et al., 2010) found that the CD4 counts increase after one day of drug initiation even before the viral load decline. This suggested that the rise of CD4 counts is possibly due to redistribution of CD4 cells from lymphoid tissues rather than regeneration of these cells. Notably, niegher

The CCR5 gene codes for a protein found on the surface of white blood cells that acts as a receptor for chemokines. The HIV virus, strain R5-tropic virus, initially uses the CCR5 chemokine receptor to attach to the CD4+ helper T-cells. The Berlin patient showed how a CCR5-negative hematopoietic stem/ progenitor cells (HSC) from a CCR5 ∆ 32 donor can be used to generate HIV-1 resistant CD4+ helper T-cells.3 Mice models using in vivo studies have also shown ZFNs to be very effective in creating this CCR5 ∆ 32 mutation and ultimately suppressing the HIV-1 replication. Holt and collegues3 performed a study using a mice model to demonstrate the use of ZFN-modified autologous HSC as a clinical approach to treat

Human immunodeficiency virus (HIV) is serious public health problem worldwide. HIV weakens a person’s immune system by infecting the body’s T cells. ("About HIV/AIDS | HIV Basics | HIV/AIDS | CDC", 2016) HIV also attacks and kills CD4 white blood cells, which play an important role in protecting the body from infections. ("Immune System 101", 2016)

CCR5 gene encodes a receptor protein on the white blood cells that is involved in the entry of many forms of HIV virus into the cell. As of today, an estimated 10-20% of the Caucasian population possesses a mutated copy of CCR5 gene, which is also called CCR5-∆32. This mutated CCR5 gene contains a 32-base pair deletion. If an individual has

The Human Immune system is made up of a variety of chemical and cellular components that are classified as either innate or adaptive immunity. The cellular immune response to the bubonic plague is carried out through the innate response as the bacterium is able to avoid the adaptive response by infecting macrophages in the host’s body. Similarly, the immune response to HIV infection is not able to reach the adaptive response, as the virus infects the body and destroys vital CD4 cells which in turn damage the immune system itself. Furthermore, the immune system relies heavily on the action of B and T cells, which are antigen-specific cellular immune responses to battle the HIV virus. Though it is unable to completely rid the host of the virus,

AIDS (Acquired immunodeficiency syndrome) is disease caused HIV (human immunodeficiency viruses). This research paper describes the evolution and origination of HIV and AIDS. There are two types of HIVs. These are called HIV-1 and HIV-2. HIVs result multiple cross species transmission from SIV (simian immunodeficiency viruses) that is viruses that infects primates. HIV-1 comes from SIV from chimpanzees whereas HIV-2 comes from sooty mangabeys. HIV-1 has four sub groups these includes M, N, O, and P. Each of groups has resulted from independent cross-species transmission event. Group M is the most virulent, and it is the first to be discovered. HIV-2 has groups that ranges from A to H. SIV are infecting West Africa primates. This fact is based on the first pandemic HIV-1 has emerged in colonial West African, and most researchers have sampled primates from this region only. Newly emerged SIVs are resulted from multiple cross species transmission and recombination. The cross species transmission occurs from non-humans to humans through eating bushmeat. The cross transmission influenced by host restriction factors, but HIVs were able to pass this barriers. Most SIV are non-pathogenic to the host; however, there is some evidence that some are pathogenic to their host. The age of the virus determined by using molecular clock method. Other studies have estimated the evolutionary timescale with same age as

The ability of the virus to choose its co-receptor is called viral tropism and determines its virulence and disease progression rate. If the virus binds with the co-receptor CCR5 it is called macrophage-tropic (M-tropic) and characterizes most HIV infections. The M-tropic variant is regarded as less virulent because it is nonsyncytial. Some mutations of the CCR5 gene lead to a partial immunity to the virus and can slow the disease and in some cases prevent infection of the M-tropic HIV varient. Also patients with high levels of CCR5 soluble chemokines are more resistant to the virus.

HIV primarily targets components of the human immune system that express the CD4 protein as a surface receptor, such as CD4+ T cells, which are mature T helper cells that express the protein on their surface, macrophages, and dendritic cells. HIV gains entry into these cells through interaction of the virion’s gp120 protein with the CD4 receptor molecule on the target and also, secondarily, with chemokine co-receptors, including CCR5 and CXCR4.

The genetic variations lead to different level of disease susceptibility to different levels in humans. In people with more resistance, the virus entry and the intracellular replication is affected by the polymorphic variants in the loci (O’Brien et al 2004). Even though there is difference in susceptibility, the escape of virus from cytotoxic T lymphocyte (CTL) takes place leading to disease progression (Leslie et al., 2004).

Resistant viruses can recognize, bind to and utilize the maraviroc/CCR5 complex for entry. Amino acid mutations in gp120 alters the way the protein interacts with CCR5. These modifications cause resistant viruses to be heavily reliant on the CCR5 N-terminus for entry (Roche et al 2015). There are two mutations on maraviroc resistant R5 HIV. These mutations replace Ala316 and Ile323 with Thr316 and Val323 on the V3 loop of the wild type HIV-1 CCR5 tropic strain. The Val323 mutation in the V3 loop of gp120 changes the secondary structure of the V3 loop making the loop less rigid and permits altered interactions with the N-terminus that allows for HIV-1 entry. A loss of beta sheets in the stem of the V3 loop occurs with the presence of the Val323 mutation. In addition, the smaller valine side chain may reduce steric interference and permit closer interaction with the residues on the N-terminus of CCR5. Thus, the Val323 mutation makes the V3 loop more fluid, allowing for closer interactions with the N-terminal of CCR5. In the presence of Maraviroc, HIV-1 resistant strains become considerably dependent on the interaction with N-terminal residues Try3, Tyr10, Tyr13, Tyr14, Tyr15, Glu 18, and Asp11.

To investigate the distribution of PI-induced mutational changes in HIV-1 across Gag and protease regions, Codoner et al. sequenced the HIV-1 Gag-protease coding region from longitudinal plasma samples from four patients receiving PI treatment over a 9-year period. Sequence analysis confirmed that HIV-1, in response to PIs, demonstrates a stepwise accumulation of Gag cleavage site mutations (CSM) at the following positions: V128I in the p17/p24 junction; S373P and I376V at the p2/NC junction; A431V at the NC/p1 junction; K436R at the NC/p1 junction and P453A at the p1/p6 junction (Codoner et al, 2017). Of these Gag CSM, A431V and K436R have been previously associated with drug resistance mutations in the protease and V128I, A431V, K436R

There has been countless number of efforts to develop an effective gene transfer approach to treat HIV-1 infections globally. Many transgenes have been identified to inhibit in vitro HIV-1 infections. As drug resistant HIV-1 is increasingly common even with patients receiving HAART, designing drug treatment methods have been challenging. Therefore, investigation into new therapeutic approaches should continue. Gene delivery plays an important supporting role developing potential therapies directed towards HIV-1 infections. The goals of the anti-HIV-1 gene therapy are to deliver transgenes to directly susceptible cells, Immunize against HIV-1 antigens, inhibit HIV-1 proliferation in target organs, and deliver to Hematopoietic Progenitor Cells. Delivering transgenes to susceptible cells will make them resistant to HIV-1 infections and inhibit viral replication. When CCR5 a major coreceptor for HIV was disrupted in the “Berlin Patient” led to the revival of gene therapy. The naturally occurring CCR5-Δ32 mutation that results in a frameshift mutation dislocates the CCR5 expression on the cell surface. The “Berlin patient” who was HIV+ patient with lymphoma was transplanted with bone marrow from a donor with CCR5-Δ32 mutation and became ‘cured’ of HIV. But as only a small general population with CCR5-Δ32 mutation can be identified alternative methods must be identified for gene therapy.

Human chromosome 3p21–22 harbors a cluster of chemokine receptor genes, several of which serve as major or minor co-receptors of HIV-1 [1]. The genetic associations of CCR5 and CCR2 gene polymorphisms with HIV-1 pathogenesis are well known [2-5], but any potential role of variation in other regions of the cluster is largely unknown. An intergenic SNP (rs1015164 A/G) downstream of the CCRL2 gene was shown to associate with HIV viral load control [6] and progression to AIDS [7] in two independent cohorts of HIV-infected patients. Importantly, the SNP showed genome-wide significant association with HIV outcomes in meta-analyses that collectively examined genotyping data from 6,315 HIV-infected patients [8]. The SNP is in close genomic proximity to a non-coding RNA gene RP-11-24F11.2 (Fig. S1). We were able to detect and quantify the polyadenylated lncRNA transcript in the total RNA from peripheral blood lymphocytes (PBLs) using quantitative PCR (qPCR). Specificity of the primers was confirmed by sequencing of the amplicons. We designated this lncRNA as Lnc11.2. The rs1015164A allele, which associated with higher viral loads (OR=1.4, p=3.3 ×10-5) [6] and more rapid disease progression (HR=1.4, p=8.6 ×10-6) [7] correlated with higher expression levels of Lnc11.2 in PBLs (Fig. 1).