• artificial intelligence
• big data
• data analysis
• data diversity and complexity
• data standardization
• viral infectious diseases

• HIV infection
• HIV/TB coinfection
• IL-10
• INF-γ
• Il-1β
• TNF-α
• tuberculosis recurrence

• antiretroviral drugs
• human immunodeficiency virus (HIV)
• progesterone
• toll-like receptors (TLRs)
• β-estradiol

• Bioinformatics
• Genetics
• Immunity

• MC_PC_17228 Medical Research Council
• R01 DC004212 NIDCD NIH HHS
• R01 DA009532 NIDA NIH HHS
• R01 DA026141 NIDA NIH HHS
• R21 AI154956 NIAID NIH HHS
• HHSN268200782096C NHLBI NIH HHS
• R01 AG004212 NIA NIH HHS
• MC_QA137853 Medical Research Council

• HLA
• MHC
• antibody
• heterologous
• highly exposed persistently seronegative
• non-specific

• Autoantibodies
• Case-Control Studies
• HIV Infections
• HIV-1
• HLA Antigens
• Humans

Unique Individuals who exhibit either suppressive HIV-1 control, or the ability to maintain low viral load set-points and preserve their CD4+ T cell counts for extended time periods in the absence of antiretroviral therapy, are broadly termed HIV-1 controllers. We assessed the extent to which black South African controllers (n=9), differ from uninfected healthy controls (HCs, n=22) in terms of lymphocyte and monocyte CCR5 expression (density and frequency of CCR5-expressing cells), immune activation as well as peripheral blood mononuclear cell (PBMC) mitogen-induced chemokine/cytokine production. In addition, relative CD4+ T cell CCR5 mRNA expression was assessed in a larger group of controllers (n=20) compared to HCs (n=10) and HIV-1 progressors (n=12). Despite controllers having significantly higher frequencies of activated CD4+ and CD8+ T cells (HLA-DR+) compared to HCs, CCR5 density was significantly lower in these T cell populations (P=0.039 and P=0.064, respectively). This lower CCR5 density was largely attributable to controllers with higher VLs (>400 RNA copies/ml). Significantly lower CD4+ T cell CCR5 density in controllers was maintained (P=0.036) when HCs (n=12) and controllers (n=9) were matched for age. CD4+ T cell CCR5 mRNA expression was significantly less in controllers compared to HCs (P=0.007) and progressors (P=0.002), whereas HCs and progressors were similar (P=0.223). The levels of soluble CD14 in plasma did not differ between controllers and HCs, suggesting no demonstrable monocyte activation. While controllers had lower monocyte CCR5 density compared to the HCs (P=0.02), significance was lost when groups were age-matched (P=0.804). However, when groups were matched for both CCR5 promoter haplotype and age (n=6 for both) reduced CCR5 density on monocytes in controllers relative to HCs was highly significant (P=0.009). Phytohemagglutinin-stimulated PBMCs from the controllers produced significantly less CCL3 (P=0.029), CCL4 (P=0.008) and IL-10 (P=0.028) compared to the HCs, which was largely attributable to the controllers with lower VLs (<400 RNA copies/ml). Our findings support a hypothesis of an inherent (genetic) predisposition to lower CCR5 expression in individuals who naturally control HIV-1, as has been suggested for Caucasian controllers, and thus, likely involves a mechanism shared between ethnically divergent population groups.

• Adult
• Black People
• Disease Resistance/immunology
• Female
• HIV Infections/immunology
• HIV-1
• Humans
• Male
• Middle Aged
• Receptors, CCR5/biosynthesis
• South Africa
• T-Lymphocytes/immunology

Staufen, the RNA-binding family of proteins, affects various steps in the Human Immuno-Deficiency Virus (HIV-1) replication cycle. While our previous study established Staufen-2–HIV-1 Rev interaction and its role in augmenting nucleocytoplasmic export of RRE-containing viral RNA, viral incorporation of Staufen-2 and its effect on viral propagation were unknown. Here, we report that Staufen-2 interacts with HIV-1 Gag and is incorporated into virions and that encapsidated Staufen-2 boosted viral infectivity. Further, Staufen-2 gets co-packaged into virions, possibly by interacting with host factors Staufen-1 or antiviral protein APOBEC3G, which resulted in different outcomes on the infectivity of Staufen-2-encapsidated virions. These observations suggest that encapsidated host factors influence viral population dynamics and infectivity. With the explicit identification of the incorporation of Staufen proteins into HIV-1 and other retroviruses, such as Simian Immunodeficiency Virus (SIV), we propose that packaging of RNA binding proteins, such as Staufen, in budding virions of retroviruses is probably a general phenomenon that can drive or impact the viral population dynamics, infectivity, and evolution.

• HIV-1 Gag
• Human Immunodeficiency Virus (HIV)
• Staufen-2
• ribonucleoprotein complexes (RNPs)
• viral incorporation
• virus-host interaction

• Cell Line
• Gene Products, gag/genetics
• Gene Products, gag/metabolism
• HIV Infections/genetics
• HIV Infections/metabolism
• HIV Infections/virology
• HIV-1/genetics
• HIV-1/pathogenicity
• HIV-1/physiology
• Host-Pathogen Interactions
• Humans
• Nerve Tissue Proteins/genetics
• Nerve Tissue Proteins/metabolism
• Protein Binding
• RNA-Binding Proteins/genetics
• RNA-Binding Proteins/metabolism
• Viral Genome Packaging
• Virulence

Tuberculosis (TB) and HIV have profound effects on the immune system, which can lead to the activation of viral replication and negatively regulate the activation of T cells. Dysregulation in the production of cytokines necessary to fight HIV and M. tuberculosis may ultimately affect the results of the treatment and be important in the pathogenesis of HIV infection and TB. This work presents the results of a study of the expression of pro- and anti-inflammatory cytokines (IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, IL-1RA) in drug-naïve patients with dual infection of HIV/TB at the late stages of HIV-infection, with newly diagnosed HIV and TB, and previously untreated HIV in the process of receiving antiretroviral (ART) and TB treatment vs. a cohort of patients with HIV monoinfection and TB monoinfection. The study revealed that during a double HIV/TB infection, both Th1 and Th2 immune responses are suppressed, and a prolonged dysregulation of the immune response and an increased severity of the disease in pulmonary/extrapulmonary tuberculosis is observed in HIV/TB co-infection. Moreover, it was revealed that a double HIV/TB infection is characterized by delayed and incomplete recovery of immune activity. High levels of IL-6 were detected in patients with HIV/TB co-infection before initiation of dual therapy (2.1-fold increase vs. HIV), which persisted even after 6 months of treatment (8.96-fold increase vs. HIV), unlike other cytokines. The persistent enhanced expression of IL-6 in patients with dual HIV/TB co-infection allows the consideration of it as a potential marker of early detection of M. tuberculosis infection in HIV-infected individuals. The results of multivariate regression analysis showed a statistical trend towards an increase in the incidence of IRIS in patients with high IL-1Ra levels (in the range of 1550–2500 pg/mL): OR = 4.3 (95%CI 3.7–14.12, p = 0.53), which also allows IL-1Ra to be considered as a potential predictive biomarker of the development of TB-IRIS and treatment outcomes.

• ART
• HIV
• HIV/TB co-infection
• cytokine profile
• immune reconstitution inflammatory syndrome
• tuberculosis

Paradoxically, early host responses to infection include the upregulation of the antiphagocytic molecule, CD47. This suggests that CD47 blockade could enhance antigen presentation and subsequent immune responses. Indeed, mice treated with anti-CD47 monoclonal antibody following lymphocytic choriomeningitis virus infections show increased activation of both macrophages and dendritic cells (DCs), enhancement of the kinetics and potency of CD8⁺ T cell responses, and significantly improved virus control. Treatment efficacy is critically dependent on both APCs and CD8⁺ T cells. In preliminary results from one of two cohorts of humanized mice infected with HIV-1 for 6 weeks, CD47 blockade reduces plasma p24 levels and restores CD4⁺ T cell counts. The results indicate that CD47 blockade not only enhances the function of innate immune cells but also links to adaptive immune responses through improved APC function. As such, immunotherapy by CD47 blockade may have broad applicability to treat a wide range of infectious diseases.

Cham et al. describe a way to enhance natural immune responses to infections by blocking interactions between two molecules (CD47 and SIRPα) that normally put brakes on the immune system. Since this therapy targets the immune system, it could have broad applicability against a wide range of infectious agents.

• CD47
• HIV-1
• LCMV
• adaptive immunity
• checkpoint inhibitors
• dendritic cells
• innate immunity

• Antiretroviral therapy
• Astrocyte
• Blood-brain barrier
• Buprenorphine
• C-C motif chemokine receptor 5 (CCR5)
• COVID-19
• Cytochrome P450 3A4 (CYP 3A4)
• Endogenous opioid system of peptides and receptors
• Functional selectivity/biased agonism
• HIV-associated neurocognitive disorders
• Maladaptive neuroplasticity
• Methadone
• Microglia
• Oligodendroglia
• P-glycoprotein
• Pro-brain-derived neurotrophic factor (pro-BDNF)
• Synaptodendritic degeneration
• neuroHIV
• μ-Opioid receptor (OPRM1)

• AIDS Dementia Complex/complications
• COVID-19
• HIV Infections/complications
• HIV-1/immunology
• Humans
• Opioid Epidemic
• Opioid-Related Disorders/epidemiology

• R01 DA018633 NIDA NIH HHS
• R01 DA044939 NIDA NIH HHS
• R01 DA045596 NIDA NIH HHS
• R01 DA045588 NIDA NIH HHS
• R01 DA034231 NIDA NIH HHS
• R21 DA045630 NIDA NIH HHS
• R01 DA044855 NIDA NIH HHS
• National Institute on Drug Abuse

Development of novel antiviral molecules from the beginning costs an average of $350 million to $2 billion per drug, and the journey from the laboratory to the clinic takes about 10–15 years. Utilization of drug repurposing approaches has generated substantial interest in order to overcome these drawbacks. A drastic reduction in the failure rate, which otherwise is ~92%, is achieved with the drug repurposing approach. The recent exploration of the drug repurposing approach to combat the COVID-19 pandemic has further validated the fact that it is more beneficial to reinvestigate the in-practice drugs for a new application instead of designing novel drugs. The first successful example of drug repurposing is zidovudine (AZT), which was developed as an anti-cancer agent in the 1960s and was later approved by the US FDA as an anti-HIV therapeutic drug in the late 1980s after fast track clinical trials. Since that time, the drug repurposing approach has been successfully utilized to develop effective therapeutic strategies against a plethora of diseases. Hence, an extensive application of the drug repurposing approach will not only help to fight the current pandemics more efficiently but also predict and prepare for newly emerging viral infections. In this review, we discuss in detail the drug repurposing approach and its advancements related to viral infections such as Human Immunodeficiency Virus (HIV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

• COVID-19
• HIV
• USFDA
• drug repurposing/reprofiling
• zidovudine

• African American
• HIV risk
• Risky sexual behavior
• STI
• Youth

• Adolescent
• Adult
• Black or African American
• Female
• HIV Infections/epidemiology
• Healthcare Disparities/standards
• Heterosexuality
• Humans
• Male
• Sexually Transmitted Diseases/epidemiology
• Social Environment
• United States
• Young Adult

• P30 DA027827 NIDA NIH HHS
• R25 DA035163 NIDA NIH HHS
• K01 DA043654 NIDA NIH HHS
• F31 DA044728 NIDA NIH HHS

Human immunodeficiency virus type 1 (HIV-1) subtype C (C-HIV) is the most prevalent form of HIV-1 globally, accounting for approximately 50% of infections worldwide. C-HIV is the predominant and near-exclusive subtype in the low resource regions of India and Southern Africa. Given the vast diversity of HIV-1 subtypes, it is curious as to why C-HIV constitutes such a large proportion of global infections. This enriched prevalence may be due to phenotypic differences between C-HIV isolates and other viral strains that permit enhanced transmission efficiency or, pathogenicity, or might due to the socio-demographics of the regions where C-HIV is endemic. Here, we compare the mechanisms of C-HIV pathogenesis to less prominent HIV-1 subtypes, including viral genetic and phenotypic characteristics, and host genetic variability, to understand whether evolutionary factors drove C-HIV to predominance.

• HIV-1
• Pathogenesis
• Subtype C
• Transmission

• AIDS
• FAS
• FASL
• HIV-1
• IL6
• polymorphisms

• Iran
• chemokine receptor R5 (CCR5)
• human immunodeficiency virus-1 (HIV-1)

Molecular epidemiological study of human immunodeficiency virus drug-resistant (HIVDR) markers is challenging in areas where the dominant subtype is non-B.

Here we provide molecular data for HIVDR in the CRF01_AE subtype in Bali, Indonesia.

Seventy patients were enrolled in this study and grouped into treatment failure and treatment naïve groups. The full-length pol gene was amplified using nested reverse transcriptase polymerase chain reaction and the product was then sequenced. The readable sequence was then subjected to Stan-ford HIV Drug Resistance Database genotyping.

We found that clinical classification was in accordance with the presence of HIVDR markers in the pol gene. Independent of therapy history, the treatment failure group showed resistance markers against nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase in-hibitors (NNRTI), ranging from 72%–100% of patients. Only a small proportion of naïve patients harbored HIV with drug resistance markers to NNRTI. No protease inhibitor-resistant marker was found in either patient group. Molecular marker mutations, which were found in more than 50% of treatment failure patients, were M184V (100%), T215A/Y/F (88.2%), D67N/G (76.5%), and M41L (58.8%).

The protocol used in this study to determine genetic markers of HIVDR based on sub-type B can be applied for the rapid determination of resistance of the CRF01_AE subtype. All patients with progressive clinical signs and increased viral load should be recommended to undergo second-line treatment of the ARV regimen.

• Bali
• CRF01_AE
• Human Immunodeficiency Virus (HIV)
• naïve
• nucleoside reverse transcriptase inhibitors (NRTI)
• treatment failure.

• PAGE
• diversity
• fine mapping
• genomics
• multiethnic
• transethnic

• classical human leukocyte antigens
• hepatitis C virus and immune regulation
• human immunodeficiency virus
• human leukocyte antigen
• major histocompatibility complex
• non-classical human leukocyte antigens

• Env mutant
• HIV-1
• cell dependence
• cell-associated viruses
• reversion

Measuring the altered gene expression level and identifying differentially expressed genes/proteins during HIV infection, replication and latency is fundamental for broadening our understanding of the mechanisms of HIV infection and T-cell dysfunction. Such studies are crucial for developing effective strategies for virus eradication from the body. Inspired by the availability and enrichment of gene expression data during HIV infection, replication and latency, in this study, we proposed a novel compendium termed HIVed (HIV expression database; http://hivlatency.erc.monash.edu/) that harbours comprehensive functional annotations of proteins, whose genes have been shown to be dysregulated during HIV infection, replication and latency using different experimental designs and measurements. We manually curated a variety of third-party databases for structural and functional annotations of the protein entries in HIVed. With the goal of benefiting HIV related research, we collected a number of biological annotations for all the entries in HIVed besides their expression profile, including basic protein information, Gene Ontology terms, secondary structure, HIV-1 interaction and pathway information. We hope this comprehensive protein-centric knowledgebase can bridge the gap between the understanding of differentially expressed genes and the functions of their protein products, facilitating the generation of novel hypotheses and treatment strategies to fight against the HIV pandemic.

• Antiretroviral Therapy, Highly Active
• Antithrombin III/genetics
• Antithrombin III/immunology
• Antiviral Agents/therapeutic use
• Brazil
• CD4 Lymphocyte Count
• Chemokines/genetics
• Chemokines/immunology
• Cohort Studies
• Cross-Priming/immunology
• Cytokines/genetics
• Cytokines/immunology
• Gene Expression Profiling/methods
• HIV Infections/drug therapy
• HIV Infections/genetics
• HIV Infections/immunology
• HIV Long-Term Survivors
• HIV-1/drug effects
• HIV-1/immunology
• HLA-B Antigens/immunology
• Host-Pathogen Interactions/drug effects
• Host-Pathogen Interactions/immunology
• Humans
• Leukocytes, Mononuclear/drug effects
• Leukocytes, Mononuclear/immunology
• Leukocytes, Mononuclear/metabolism
• Reverse Transcriptase Polymerase Chain Reaction
• Transcriptome/drug effects
• Transcriptome/immunology

• FAPESP
• CNPQ

• CD4–gp120 interface
• molecular dynamics simulations
• protein–ligand docking
• protein–protein interaction network
• structure prediction

• AIDS
• HIV-1
• antiretroviral therapy
• epidemiology
• pathology
• treatment
• virus entry

• R01 AI118732 NIAID NIH HHS
• T32 AI007046 NIAID NIH HHS

Killer cell immunoglobulin-like receptors (KIR) are the most polymorphic receptors of natural killer (NK) cells. Their activity diversifies the functions of NK cells in the antiviral immune response, so the presence of certain KIR may affect transmission of HIV-1. The aim of the study was to evaluate the influence of KIR genes on the susceptibility to HIV-1 infection in the Polish population depending on the route of exposure. We determined the frequencies of activating (2DS1, 2DS2, 2DS3, 2DS4f, 2DS4del, 2DS5, 3DS1) and inhibitory (2DL1, 2DL2, 2DL3, 2DL5, 3DL1) KIRs in HIV-1-positive patients (n = 459), individuals exposed to HIV-1 but uninfected (EU, n = 118) and in uninfected, healthy blood donors (BD, n = 98). Analysis was performed using stepwise logistic regression. Apart from KIRs, CCR5-∆32, and CCR2-64I, alleles were also analyzed, as we knew or suspected that these features could affect susceptibility to HIV infection. The regression confirmed the protective effect of CCR5-∆32 (OR = 0.25, p = 0.006) and CCR2-64I (OR = 0.59, p = 0.032) against HIV infection. Among KIR genes, 2DL3 was found to be a protective factor (OR = 0.30, p = 0.015). A similar effect was seen for 3DS1 but only in intravenous drug users (IDUs) (OR = 0.30, p = 0.019), not in sexually exposed people. 2DL5 was found to be a factor facilitating HIV infection (OR = 2.13, p = 0.013). A similar effect was observed for 2DL2 but only in females (OR = 2.15, p = 0.040), and 2DS1 in IDUs (OR = 3.03, p = 0.022). Our results suggest a beneficial role of KIR3DS1 and 2DL3 supporting resistance to HIV infection and a harmful effect of 2DS1, 2DL5, and 2DL2 genes promoting HIV acquisition.

• Chemokine receptors
• Host genetics
• Killer cell immunoglobulin-like receptors (KIR)
• Susceptibility to HIV infection

Human T-cell leukemia virus type 1 (HTLV-1), hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) are prevalent worldwide, and share similar means of transmission. These infections may influence each other in evolution and outcome, including cancer or immunodeficiency. Many studies have reported the influence of genetic markers on the host immune response against different persistent viral infections, such as HTLV-1 infection, pointing to the importance of the individual genetic background on their outcomes. However, despite recent advances on the knowledge of the pathogenesis of HTLV-1 infection, gaps in the understanding of the role of the individual genetic background on the progress to disease clinically manifested still remain. In this scenario, much less is known regarding the influence of genetic factors in the context of dual or triple infections or their influence on the underlying mechanisms that lead to outcomes that differ from those observed in monoinfection. This review describes the main factors involved in the virus–host balance, especially for some particular human leukocyte antigen (HLA) haplotypes, and other important genetic markers in the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and other persistent viruses, such as HIV and HCV.

• HCV
• HIV-1
• HTLV-1
• genetic factors

• Genetic Markers
• HIV Infections/genetics
• HIV Infections/virology
• HIV-1/physiology
• HTLV-I Infections/genetics
• HTLV-I Infections/virology
• Human T-lymphotropic virus 1/physiology
• Humans

Co-infection with Mycobacterium tuberculosis accelerates progression from HIV to AIDS. Our previous studies showed that M. tuberculosis complex, unlike M. smegmatis, enhances TLR2-dependent susceptibility of CD4+ T cells to HIV. The M. tuberculosis complex produces multiple TLR2-stimulating lipoproteins, which are absent in M. smegmatis. M. tuberculosis production of mature lipoproteins and TLR2 stimulation is dependent on cleavage by lipoprotein signal peptidase A (LspA). In order to determine the role of potential TLR2-stimulating lipoproteins on mycobacterial-mediated HIV infectivity of CD4+ T cells, we generated M. smegmatis recombinant strains overexpressing genes encoding various M. bovis BCG lipoproteins, as well as a Mycobacterium bovis BCG strain deficient in LspA (ΔlspA). Exposure of human peripheral blood mononuclear cells (PBMC) to M. smegmatis strains overexpressing the BCG lipoproteins, LprF (p<0.01), LprH (p<0.05), LprI (p<0.05), LprP (p<0.001), LprQ (p<0.005), MPT83 (p<0.005), or PhoS1 (p<0.05), resulted in increased HIV infectivity of CD4+ T cells isolated from these PBMC. Conversely, infection of PBMC with ΔlspA reduced HIV infectivity of CD4+ T cells by 40% relative to BCG-infected cells (p<0.05). These results may have important implications for TB vaccination programs in areas with high mother-to-child HIV transmission.

• Adult
• Aspartic Acid Endopeptidases/metabolism
• Bacterial Proteins/metabolism
• CD4-Positive T-Lymphocytes/metabolism
• CD4-Positive T-Lymphocytes/virology
• Cells, Cultured
• Disease Susceptibility
• Gene Knock-In Techniques
• Genes, Bacterial
• HIV-1/physiology
• Host-Pathogen Interactions
• Humans
• Lipoproteins/metabolism
• Mycobacterium bovis/genetics
• Mycobacterium bovis/metabolism
• Mycobacterium smegmatis/genetics
• Mycobacterium smegmatis/metabolism
• Mycobacterium tuberculosis/physiology
• Protein Sorting Signals
• Recombinant Fusion Proteins/metabolism
• Toll-Like Receptor 2/metabolism
• Virulence

• K23 HD056957 NICHD NIH HHS
• P30 AI094189 NIAID NIH HHS
• K23HD056957 NICHD NIH HHS
• P30AI094189 NIAID NIH HHS

Host and viral factors deeply influence the human immunodeficiency virus (HIV) disease progression. Among them human leukocyte antigen (HLA) locus plays a key role at different levels. In fact, genes of the HLA locus have shown the peculiar capability to modulate both innate and adaptive immune responses. In particular, HLA class I molecules are recognized by CD8⁺ T-cells and natural killers (NK) cells towards the interaction with T cell receptor (TCR) and Killer Immunoglobulin Receptor (KIR) 3DL1 respectively. Polymorphisms within the different HLA alleles generate structural changes in HLA class I peptide-binding pockets. Amino acid changes in the peptide-binding pocket lead to the presentation of a different set of peptides to T and NK cells. This review summarizes the role of HLA in HIV progression toward acquired immunodeficiency disease syndrome and its receptors. Recently, many studies have been focused on determining the HLA binding-peptides. The novel use of immune-informatics tools, from the prediction of the HLA-bound peptides to the modification of the HLA-receptor complexes, is considered. A better knowledge of HLA peptide presentation and recognition are allowing new strategies for immune response manipulation to be applied against HIV virus.

• Human immunodeficiency virus progression
• Human leukocyte antigen
• Epitope
• Immunoinformatics
• CD8⁺ T lymphocytes

Some individuals remain HIV-1 antibody and PCR negative after repeated exposures to the virus, and are referred to as HIV-exposed seronegatives (HESN). However, the causes of resistance to HIV-1 infection in cases other than those with a homozygous CCR5Δ32 deletion are unclear. We hypothesized that human p21^WAF1/CIP1 (a cyclin-dependent kinase inhibitor) could play a role in resistance to HIV-1 infection in HESN, as p21 expression has been associated with suppression of HIV-1 in elite controllers and reported to block HIV-1 integration in cell culture. We measured p21 RNA expression in PBMC from 40 HESN and 40 low exposure HIV-1 seroconverters (LESC) prior to their infection using a real-time PCR assay. Comparing the 20 HESN with the highest exposure risk (median = 111 partners/2.5 years prior to the 20 LESC with the lowest exposure risk (median = 1 partner/2.5 years prior), p21 expression trended higher in HESN in only one of two experiments (P = 0.11 vs. P = 0.80). Additionally, comparison of p21 expression in the top 40 HESN (median = 73 partners/year) and lowest 40 LESC (median = 2 partners/year) showed no difference between the groups (P = 0.84). There was a weak linear trend between risk of infection after exposure and increasing p21 gene expression (R² = 0.02, P = 0.12), but again only in one experiment. Hence, if p21 expression contributes to the resistance to viral infection in HESN, it likely plays a minor role evident only in those with extremely high levels of exposure to HIV-1.

• Cyclin-Dependent Kinase Inhibitor p21/genetics
• HIV Infections/transmission
• HIV Infections/virology
• HIV Seronegativity
• HIV-1
• Humans
• RNA/genetics
• Risk Factors
• Sexual Partners
• Unsafe Sex

• U01 AI035042 NIAID NIH HHS
• U01-AI35040 NIAID NIH HHS
• U01-AI35042 NIAID NIH HHS
• U01 AI035041 NIAID NIH HHS
• P01 AI057005 NIAID NIH HHS
• U01-AI35039 NIAID NIH HHS
• U01 AI035040 NIAID NIH HHS
• U01 AI035039 NIAID NIH HHS
• UM1-AI35043 NIAID NIH HHS
• P30 MH058107 NIMH NIH HHS
• UM1 AI035043 NIAID NIH HHS
• U01-AI35041 NIAID NIH HHS
• R37-047734 PHS HHS

The deciphering of cellular networks to determine susceptibility to infection by HIV or the related simian immunodeficiency virus (SIV) is a major challenge in infection biology.

Here, we have compared gene expression profiles of a human CD4⁺ T cell line at 24 h after infection with a cell line of the same origin permanently releasing SIV_mac. A new knowledge-based-network approach (Inter-Chain-Finder, ICF) has been used to identify sub-networks associated with cell survival of a chronically SIV-infected T cell line. Notably, the method can identify not only differentially expressed key hub genes but also non-differentially expressed, critical, ‘hidden’ regulators. Six out of the 13 predicted major hidden key regulators were among the landscape of proteins known to interact with HIV. Several sub-networks were dysregulated upon chronic infection with SIV. Most prominently, factors reported to be engaged in early stages of acute viral infection were affected, e.g. entry, integration and provirus transcription and other cellular responses such as apoptosis and proliferation were modulated. For experimental validation of the gene expression analyses and computational predictions, individual pathways/sub-networks and significantly altered key regulators were investigated further. We showed that the expression of caveolin-1 (Cav-1), the top hub in the affected protein-protein interaction network, was significantly upregulated in chronically SIV-infected CD4⁺ T cells. Cav-1 is the main determinant of caveolae and a central component of several signal transduction pathways. Furthermore, CD4 downregulation and modulation of the expression of alternate and co-receptors as well as pathways associated with viral integration into the genome were also observed in these cells. Putatively, these modifications interfere with re-infection and the early replication cycle and inhibit cell death provoked by syncytia formation and bystander apoptosis.

Thus, by using the novel approach for network analysis, ICF, we predict that in the T cell line chronically infected with SIV, cellular processes that are known to be crucial for early phases of HIV/SIV replication are altered and cellular responses that result in cell death are modulated. These modifications presumably contribute to cell survival despite chronic infection.

The online version of this article (doi:10.1186/1743-422X-11-152) contains supplementary material, which is available to authorized users.

• Environmental contamination
• Free-living pathogens
• Immuno-epidemiology
• Linked dynamics
• Mathematical model
• Schistosomiasis

• Communicable Diseases/transmission
• Environment
• Host-Pathogen Interactions
• Humans
• Models, Theoretical
• Schistosomiasis/transmission

• AK1
• HIV-1
• PRKACB
• RNAi screen
• kinases
• long terminal repeat

• Adenylate Kinase/genetics
• Adenylate Kinase/metabolism
• Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/genetics
• Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/metabolism
• Gene Expression Regulation, Viral
• Gene Regulatory Networks
• HEK293 Cells
• HIV Long Terminal Repeat/genetics
• HIV-1/genetics
• HIV-1/growth & development
• High-Throughput Nucleotide Sequencing/methods
• Host-Pathogen Interactions
• Humans
• Oligonucleotide Array Sequence Analysis
• Protein Interaction Maps
• Protein Kinases/genetics
• Protein Kinases/metabolism
• RNA Interference
• RNA, Small Interfering/genetics
• RNA, Small Interfering/metabolism
• Receptor, EphB2/genetics
• Receptor, EphB2/metabolism
• Signal Transduction
• Transfection
• Virus Replication

• Adult
• Analysis of Variance
• Antiretroviral Therapy, Highly Active/methods
• CD4 Lymphocyte Count
• CD4-Positive T-Lymphocytes/pathology
• CD4-Positive T-Lymphocytes/virology
• Female
• Follow-Up Studies
• Functional Laterality/physiology
• HIV Infections/drug therapy
• HIV Infections/pathology
• HIV Infections/physiopathology
• Humans
• Male
• Middle Aged
• Prospective Studies
• Statistics as Topic

• Cell Line
• DNA, Mitochondrial/genetics
• Green Fluorescent Proteins
• HIV Infections/genetics
• HIV Infections/metabolism
• Humans
• Microscopy, Confocal
• Oxidative Phosphorylation
• Real-Time Polymerase Chain Reaction

• P30AI073961 NIAID NIH HHS
• R01 AI039973 NIAID NIH HHS
• R01 GM071775 NIGMS NIH HHS
• P30 AI073961 NIAID NIH HHS
• AI-39973 NIAID NIH HHS

• A1T1
• Genotypes frequencies
• HIV
• infection

Patients demonstrate notable variations in disease progression following human immunodeficiency virus (HIV) infection. We aimed to identify ZNRD1 and RNF39 genetic variants linked to AIDS progression. We conducted a genetic association study in HIV-1-infected Han Chinese patients residing in Taiwan. The clinical characteristics of 143 HIV-1-infected patients were measured, and patients were split into 2 groups: AIDS progression and AIDS non-progression. Genotyping of ZNRD1 and RNF39 was performed in all participants. We found that patients in the AIDS progression group had higher HIV-1 viral loads and lower CD4 cell counts than did patients in the AIDS non-progression group. The frequency of the AA genotype of ZNRD1 (rs16896970) was lower in the AIDS progression group than in the AIDS non-progression group. Patients with AA genotypes had lower levels of HIV-1 viral loads and higher levels of CD4 cell counts than did patients with AG+GG genotypes. AIDS progression in patients with the AA group is significantly different from that in patients with the AG and GG groups by using Kaplan-Meier survival analysis. The hazard ratio for progression was lower in the AA group than in the AG and GG groups. We identified a SNP that contributes to AIDS progression in HIV-1-infected patients in this population. This SNP had a significant protective influence on AIDS progression, and polymorphisms of the ZNRD1 gene may play a role in the pathogenesis of HIV-1 infection.

Among HIV-infected individuals, co-infection with Mycobacterium tuberculosis is associated with faster progression to AIDS. We investigated the hypothesis that M. bovis BCG and M. tuberculosis (Mtb complex) could enhance susceptibility of CD4+ cells to HIV infection. Peripheral blood mononuclear cells (PBMCs) collected from healthy donors were stimulated with M. bovis BCG, M. tuberculosis CDC1551 and M. smegmatis MC²155, and stimulated CD4+ cells were infected with R5-and X4-tropic single replication-competent pseudovirus. CD4+ cells stimulated with Mtb complex showed enhanced infection with R5- and X4-tropic HIV, compared to unstimulated cells or cells stimulated with M. smegmatis (p<0.01). Treatment with TLR2 siRNA reversed the increased susceptibility of CD4+ cells with R5- and X4-tropic virus induced by Mtb complex. These findings suggest that TB infection and/or BCG vaccination may be a risk factor for HIV acquisition.

• Adult
• CD4-Positive T-Lymphocytes/immunology
• CD4-Positive T-Lymphocytes/metabolism
• CD4-Positive T-Lymphocytes/microbiology
• CD4-Positive T-Lymphocytes/virology
• Disease Susceptibility/immunology
• Disease Susceptibility/microbiology
• Gene Expression Regulation/immunology
• HIV-1/physiology
• Humans
• Mycobacterium bovis/immunology
• Mycobacterium tuberculosis/immunology
• Toll-Like Receptor 2/metabolism
• Young Adult

• Howard Hughes Medical Institute
• R01AI083125 NIAID NIH HHS
• K23 HD056957 NICHD NIH HHS
• R01 AI083125 NIAID NIH HHS
• K23HD056957 NICHD NIH HHS

Variability to HIV infection, its progression as well as responsiveness to antiretroviral therapy (ART) is observed among individuals including viraemia controllers or exposed uninfected, rapid versus slow progressors and ART responders compared to non responders. This differential responsiveness/vulnerability to HIV-1 is governed by multiple host genetic factors that include HLA, cytokines, chemokines, their receptors and others. This review highlights the influence of these genetic factors on HIV/AIDS outcome; however, in India, the information in this area is very limited and most of these genetic studies have been conducted in Caucasian and South African populations. Considering, the population specific differences in the frequencies of protective or susceptibility favouring alleles and their influence on the disease outcome, it is of utmost importance to strengthen ongoing efforts towards defining largely unknown genetic propensity in Indian population, particularly by recruitment of large cohorts of well categorized exposed uninfected individuals, rapid, long term non progressors and elite viraemic controllers. Multi-parametric analysis of these potentially interactive immunogenetic variables in these cohorts may help to define potential targets for diagnostics and therapy in a population specific manner.

• Carrier Proteins/genetics
• Cell Line
• Cells, Cultured
• DNA, Viral/analysis
• Dendritic Cells/metabolism
• Dendritic Cells/virology
• Gene Silencing
• Genes, gag
• HIV-1/genetics
• HIV-1/physiology
• Humans
• Leukocytes, Mononuclear/virology
• Protein Serine-Threonine Kinases
• Proviruses/genetics
• RNA Interference
• RNA, Messenger/metabolism
• T-Lymphocytes/metabolism
• T-Lymphocytes/virology
• Ubiquitin-Protein Ligases
• Viral Envelope Proteins/metabolism
• Virus Replication/genetics
• vpr Gene Products, Human Immunodeficiency Virus/genetics
• vpr Gene Products, Human Immunodeficiency Virus/metabolism

• AI098524 NIAID NIH HHS
• R21 AI078762 NIAID NIH HHS
• AI068493 NIAID NIH HHS
• R21 AI098524 NIAID NIH HHS
• R01 AI068493 NIAID NIH HHS
• R21 AI102822 NIAID NIH HHS
• AI078762 NIAID NIH HHS