Human Immunodeficiency Virus Strategy Research Articles

Dual role of circulating and mucosal Vδ1 T cells in the control of and contribution to persistent HIV-1 infection.

Curative strategies for human immunodeficiency virus (HIV-1) infection are hindered by incomplete characterization of the latent reservoir and limited enhancement of anti-HIV immune responses. In this study, we identified a novel dual role for peripheral and tissue-resident Vδ1 T cells within the gastrointestinal mucosa of virally suppressed people with HIV. Phenotypic analyses identified an increased frequency of highly differentiated, cytotoxic effector Vδ1 T cells that exerted potent inhibition of HIV-1 replication in vitro coinciding with direct increases in cytolytic function. Conversely, we detected an enrichment of HIV-1 DNA in tissue-resident CD4+Vδ1 T cells in situ. Despite low CD4 expression, we found circulating Vδ1 T cells also contained HIV-1 DNA which was replication-competent. We show that TCR-mediated activation of peripheral Vδ1 T cells induced de novo upregulation of CD4 providing a plausible mechanism for increased permissibility to infection. These findings highlight juxtaposing roles for Vδ1 T cells in HIV-1 persistence including significant contribution to tissue reservoirs.

Leveraging the therapeutic, biological, and self-assembling potential of peptides for the treatment of viral infections.

Peptides and peptide-based materials have an increasing role in the treatment of viral infections through their use as active pharmaceutical ingredients, targeting moieties, excipients, carriers, or structural components in drug delivery systems. The discovery of peptide-based therapeutic compounds, coupled with the development of new stabilization and formulation strategies, has led to a resurgence of antiviral peptide therapeutics over the past two decades. The ability of peptides to bind cell receptors and to facilitate membrane penetration and subsequent intracellular trafficking enables their use in various antiviral systems for improved targeting efficiency and treatment efficacy. Importantly, the self-assembly of peptides into well-defined nanostructures provides a vast library of discrete constructs and supramolecular biomaterials for systemic and local delivery of antiviral agents. We review here the recent progress in exploiting the therapeutic, biological, and self-assembling potential of peptides, peptide conjugates, and their supramolecular assemblies in treating human viral infections, with an emphasis on the treatment strategies for Human Immunodeficiency Virus (HIV).

Antiretroviral Initiation at ≥800 CD4+ Cells/mm3 Associated With Lower Human Immunodeficiency Virus Reservoir Size.

Identifying factors that determine the frequency of latently infected CD4+ T cells on antiretroviral therapy (ART) may inform strategies for human immunodeficiency virus (HIV) cure. We investigated the role of CD4+ count at ART initiation for HIV persistence on ART. Among participants of the Strategic Timing of Antiretroviral Treatment Study, we enrolled people with HIV (PWH) who initiated ART with CD4+ T-cell counts of 500-599, 600-799, or ≥ 800 cells/mm3. After 36-44 months on ART, the levels of total HIV-DNA, cell-associated unspliced HIV-RNA (CA-US HIV-RNA), and two-long terminal repeat HIV-DNA in CD4+ T cells were quantified and plasma HIV-RNA was measured by single-copy assay. We measured T-cell expression of Human Leucocyte Antigen-DR Isotype (HLA-DR), programmed death-1, and phosphorylated signal transducer and activator of transcription-5 (pSTAT5). Virological and immunological measures were compared across CD4+ strata. We enrolled 146 PWH, 36 in the 500-599, 60 in the 600-799, and 50 in the ≥ 800 CD4 strata. After 36-44 months of ART, total HIV-DNA, plasma HIV-RNA, and HLA-DR expression were significantly lower in PWH with CD4+ T-cell count ≥ 800 cells/mm3 at ART initiation compared with 600-799 or 500-599 cells/mm3. The median level of HIV-DNA after 36-44 months of ART was lower by 75% in participants initiating ART with ≥ 800 vs 500-599 cells/mm3 (median [interquartile range]: 16.3 [7.0-117.6] vs 68.4 [13.7-213.1] copies/million cells, respectively). Higher pSTAT5 expression significantly correlated with lower levels of HIV-DNA and CA-US HIV-RNA. Virological measures were significantly lower in females. Initiating ART with a CD4+ count ≥ 800 cells/mm3 compared with 600-799 or 500-599 cells/mm3 was associated with achieving a substantially smaller HIV reservoir on ART.

Evaluation of preliminary screening strategies for human immunodeficiency virus: a single center experience

Background: To compare and evaluate the available screening tests for human immunodeficiency virus (HIV) antibody screening test. Methods: A retrospective analysis of 331,968 screening specimens for HIV antibody test from the First Affiliated Hospital of Nanjing Medical University between January 2010 and April 2014 was performed. Three hundred and thirty-two cases were screened positive with the third-generation enzyme-linked immunosorbent assay (3G ELISA) and colloidal gold-immunochromatography assay (GICA) and these samples were repeat-tested by the fourth-generation ELISA (4G ELISA). Repeat tested positive samples were again confirmed by western blot (WB) analysis. Comparative study was used to analyze the effectiveness of the 3G ELISA, 4G ELISA and/or combined with GICA, respectively for screening of presence of HIV antibody. Results: Of the 332 positive 3G ELISA screening samples, 189 samples were confirmed to be positive for HIV by WB. The confirmed positive coincidence rate of 3G ELISA with WB was 57.27% and with 4G ELISA was 89.15%. The difference between the 3G and 4G ELISA in HIV antibody detection was statistically significant (P Conclusions: The 4G ELISA is a better HIV antibody screening test than 3G ELISA, especially when combined with GICA. The 4G ELISA combined with GICA appears to be a more suitable strategy for HIV antibody screening test in clinical practice.

English

In recent years safe voluntary male medical circumcision (VMMC) has been recommended by the World Health Organization (WHO) as one of the preventive strategies for human immunodeficiency virus (HIV)-infection for those countries with high HIV prevalence and low medical male circumcision rates. This study aimed to assess the level of knowledge, attitude, and acceptance of safe VMMC among male university students attending Botswana University. A survey instrument was used to collect descriptive data in this study. Out of the total number of faculties within the university (8), we purposively selected our sample from the faculty of science due to its predominant male student population of 1,045. A total of 437 students were recruited from the various departments within the faculty. A semi-structured questionnaire was used for data collection. Study results indicate that 95.4% of the participants had heard about VMMC and 64.8% of those who had heard about VMMC were uncircumcised. About 31.4% knew about the complications of VMMC. Participants having undergone VMMC were twice as likely to be aware that VMMC reduces the risk of penile cancer and that it improves penile hygiene. Participants who knew that VMMC reduces the risk of other STIs were found to be four times more likely to accept VMMC as a preventive method for HIV infection. Participants having been medically circumcised were four times more likely to disagree with the statement that VMMC decreases sexual satisfaction and ten times more likely to disagree with the statement that the tip of the penis has to be covered by the foreskin. Study findings suggest that in terms of knowledge and attitude, the most significant factor associated with men’s acceptability of VMMC was their awareness that it reduces the risk of other STIs. It is therefore concluded that even though there exist a high-level of awareness and favourable attitude towards VMMC among the young male population; such awareness does not seem to influence individuals to become medically circumcized.   Key words: Voluntary male medical circumcision, human immunodeficiency virus (HIV) prevention, sexual transmitted infections, university students.

Biomedical Strategies for Human Immunodeficiency Virus (HIV) Prevention? A New Paradigm

This article presents recent developments in biomedical interventions for prevention of sexual transmission of the human immunodeficiency virus (HIV) infection. A review of results from randomised clinical trials on the use of antiretroviral (ARV) medications and other biomedical methods to prevent the transmission and acquisition of HIV infection. Pre-exposure prophylaxis (PrEP) refers to the provision of ARV medications to uninfected persons at high risk of HIV infection either in the form of topical agents, e.g. vaginal microbicide gels, or orally administered tablets. The Caprissa study demonstrated the efficacy of vaginal microbicides, the Vaginal and Oral Interventions to Control the Epidemic (VOICE) study however was not able to confirm these results. Oral PrEP was found to be efficacious in the iPrEx study on men who have sex with men (MSM), and among heterosexual couples in the Partners-PrEP and the TDF2 studies in Africa. The HPTN 052 trial demonstrated that the provision of early ARV treatment was able to prevent transmission of HIV by 92% compared with delayed treatment. This has led to enthusiasm to roll out treatment as prevention (TasP) programmes. Encouraging results from studies on male circumcision to prevent HIV acquisition have resulted in several implementation projects in Africa. Another encouraging result has been the success, albeit modest, of the prime-boost combination RV144 vaccine trial in Thailand. New advances in prevention strategies are urgently needed to slow down the HIV pandemic. Recent developments particularly in the form of PrEP and TasP have given new hope that we will be able to achieve this goal.

Vaccine-induced T cells Provide Partial Protection Against High-dose Rectal SIVmac239 Challenge of Rhesus Macaques

Despite enormous efforts by the scientific community, an effective HIV vaccine remains elusive. To further address to what degree T cells in absence of antibodies may protect against simian immunodeficiency virus (SIV) disease progression, rhesus macaques were vaccinated intramuscularly with a chimpanzee-derived Ad vector (AdC) serotype 6 and then boosted intramuscularly with a serologically distinct AdC vector of serotype 7 both expressing Gag of SIVmac239. Animals were subsequently boosted intramuscularly with a modified vaccinia Ankara (MVA) virus expressing Gag and Tat of the homologous SIV before mucosal challenge with a high dose of SIVmac239 given rectally. Whereas vaccinated animals showed only a modest reduction of viral loads, their overall survival was improved, in association with a substantial protection from the loss of CD4(+) T cells. In addition, the two vaccinated Mamu-A*01(+) macaques controlled viral loads to levels below detection within weeks after challenge. These data strongly suggest that T cells, while unable to affect SIV acquisition upon high-dose rectal infection, can reduce disease progression. Induction of potent T-cell responses should thus remain a component of our efforts to develop an efficacious vaccine to HIV-1.

Tetraspanins in Viral Infections: a Fundamental Role in Viral Biology?

The tetraspanins are a broadly expressed superfamily of transmembrane glycoproteins with over 30 members found in humans and with homologues conserved through distantly related species, including insects, sponges, and fungi. Members of this family appear to form large integrated signaling complexes or tetraspanin-enriched microdomains (TEMs) by their association with a variety of transmembrane and intracellular signaling/cytoskeletal proteins (49). These interactions link tetraspanins to an array of physiological functions and, in consequence, to numerous endogenous pathologies, including cancer development and inherited disorders (Table ​(Table11). TABLE 1. Members of the tetraspanin superfamily with reported links to pathologiesa Tetraspanins are also known to have roles in the pathology of infectious diseases such as diphtheria, malaria, and numerous viral infections (Table ​(Table1).1). The literature currently indicates that specific tetraspanin family members are selectively associated with specific viruses and affect multiple stages of infectivity, from initial cellular attachment to syncytium formation and viral particle release. Thus, the relationship of tetraspanins with viruses appears to be particularly complex. Here, we will consider this data in the context of recent developments in tetraspanin biology, particularly in our understanding of the architecture and function of TEMs. With the benefit of recent insights into tetraspanin function in cell fusion events and intracellular trafficking, we discuss common features of tetraspanin/viral associations which indicate a fundamental role for TEMs in a number of viral infections. We will also consider the existing therapeutic strategies for human immunodeficiency virus (HIV), hepatitis C virus (HCV), and human T-cell lymphotropic virus type 1 (HTLV-1), focusing on the potential therapeutic value of targeting TEMs, using peptide reagents based on tetraspanin extracellular regions.

Analysis of hepatitis B virus dynamics and its impact on antiviral development.

Viral dynamics is the study of the population dynamics of viral infection within the body of an infected individual. It describes how viruses spread from cell to cell, with the aim of revealing the basic laws that govern the spread of the virus within the host, their interaction with the immune system, and their response to therapy. For viruses that produce a viremia, changes in the size of the virus population can be measured and followed from blood samples obtained by phlebotomy at various time intervals using very sensitive polymerase chain reaction (PCR)-based assays to quantify viral nucleic acids accurately over a dynamic range of six orders of magnitude. To analyze these data, mathematical models based on a firm understanding of the biology of the virus and its interaction with the host have been developed. Such models can often provide nonintuitive insights into the dynamics of viral infection. The advent of potent antiviral drugs for the treatment of viral diseases in recent years has facilitated the mathematical analysis of the dynamics of viral infections by providing a means for perturbing the steady state that commonly exists during chronic infection. Such studies have yielded not only insight into our understanding of the establishment, maintenance, and clearance of viral infection, but also predictors of response and principles useful in the design of more effective treatment strategies for human immunodeficiency virus (HIV) (1–4) and hepatitis C virus (HCV) (5,6) and promises to do the same for hepatitis B virus (HBV) as well. Importantly, viral dynamics analyses now offer a more sophisticated way of analyzing the response to therapy, particularly in Phase II clinical studies of short duration. Viral dynamics analysis maximizes the use of readily available data and allows different drugs, dosages and regimens to be compared more precisely. In this chapter, the basic model that has been formulated for HBV dynamics is explained and its application to the analysis of response to antiviral therapy is

Host-directed and immune-based therapies for human immunodeficiency virus infection.

This essay reviews the rationale underlying host-directed or immune-based therapeutic strategies for human immunodeficiency virus (HIV) infection and its complications. These approaches have seen only limited trial in the past 10 years, but as more is learned about the immunopathogenesis of HIV disease and as the limitations of virus-directed therapies become more apparent, the need to pursue other therapeutic avenues has become increasingly important. Moreover, properly designed trials of host-directed and immune-based therapies can provide key insights into the pathogenesis of HIV disease that may be otherwise unattainable through in vitro studies.