Bioinformatic Analysis of HIV-1 Entry and Pathogenesis

Abstract

The evolution of human immunodeficiency virus type 1 (HIV-1) with respect to co-receptor utilization has been shown to be relevant to HIV-1 pathogenesis and disease. The CCR5-utilizing (R5) virus has been shown to be important in the very early stages of transmission and highly prevalent during asymptomatic infection and chronic disease. In addition, the R5 virus has been proposed to be involved in neuroinvasion and central nervous system (CNS) disease. In contrast, the CXCR4-utilizing (X4) virus is more prevalent during the course of disease progression and concurrent with the loss of CD4+ T cells. The dual-tropic virus is able to utilize both co-receptors (CXCR4 and CCR5) and has been thought to represent an intermediate transitional virus that possesses properties of both X4 and R5 viruses that can be encountered at many stages of disease. The use of computational tools and bioinformatic approaches in the prediction of HIV-1 co-receptor usage has been growing in importance with respect to understanding HIV-1 pathogenesis and disease, developing diagnostic tools, and improving the efficacy of therapeutic strategies focused on blocking viral entry. Current strategies have enhanced the sensitivity, specificity, and reproducibility relative to the prediction of co-receptor use; however, these technologies need to be improved with respect to their efficient and accurate use across the HIV-1 subtypes. The most effective approach may center on the combined use of different algorithms involving sequences within and outside of the env-V3 loop. This review focuses on the HIV-1 entry process and on co-receptor utilization, including bioinformatic tools utilized in the prediction of co-receptor usage. It also provides novel preliminary analyses for enabling identification of linkages between amino acids in V3 with other components of the HIV-1 genome and demonstrates that these linkages are different between X4 and R5 viruses.

Central and peripheral reservoirs of feline immunodeficiency virus in cats: a review

“…Binding instigates a conformational change in Env, which facilitates subsequent binding between the cell surface expressed chemokine receptor CXCR4 and the V3 region of Env-SU [35,36]. Binding of a primary cell surface receptor to facilitate Env interactions with a surface chemokine receptor is a mode of cell entry that is also well characterized for other immunodeficiency-inducing lentiviruses such as HIV-1 and SIV [37,38].…”

“…Accordingly, HIV-1 and FIV utilize similar strategies for entry of target cells by Env binding of a primary cell surface receptor, CD4 and CD134, respectively, that facilitates Env interactions with either the CCR5 (HIV-1 only) or CXCR4 (HIV-1 and FIV) chemokine coreceptors [37,49]. Furthermore, targeting CD4+ T cells through either CD4 or CD134 surface proteins results in a similar immunopathogenesis, characterized by a progressive CD4+ T cell depletion, lymphoid depletion and immune exhaustion during the chronic phases of HIV-1 and FIV infections, respectively.…”

Specific amino acids in HIV-1 Vpr are significantly associated with differences in patient neurocognitive status

“…Neuropsychological assessments of HIV-1-infected patients currently enrolled in the CARES Cohort at the Drexel University College of Medicine (Aiamkitsumrit et al , 2014; Dampier et al , 2016; Li et al , 2011; Nonnemacher et al , 2016; Parikh et al , 2014; Shah et al , 2014) revealed a range of neurocognitive function, as indicated by GDS. Most Cohort patients for which Vpr sequences were available had GDS ≤2 (Fig.…”

“…A subset of the patients in the Drexel Medicine CARES Cohort who received CNPA (n = 112/191) had whole blood collected and processed for drug screening, plasma analysis, PBMC isolation, and genomic DNA isolation as previously described (Aiamkitsumrit et al, 2014; Li et al, 2011). Brain (head of caudate) tissues and matched spleen samples from three HIV-1-infected patients were acquired from the National NeuroAIDS Tissue Consortium (NNTC) (Morgello et al, 2001).…”

Human Immunodeficiency Virus Type 1 Cellular Entry and Exit in the T Lymphocytic and Monocytic Compartments

“…These three viral types exhibit their own preference with respect to infecting target cells due to the relative level of receptor and coreceptor proteins expressed on the cell surface. However, this coreceptor tropism classification frequently leads to confusion with the HIV-1 cellular tropism classification that classifies viral types based on primary infected target cells, which are monocyte-macrophage (M)-tropic and T-cell line (T)-tropic viruses as previously reviewed (Aiamkitsumrit et al, 2014;Gorry et al, 2004). The R5 virus preferentially utilizes CCR5 as a coreceptor and this molecule is often found on cells of monocyte-macrophage lineage as well as selected T-cell subsets, while the X4 virus favors the use of the CXCR4 molecule, which is primarily located on T cells .…”