Differential expression in human and mouse cells of human immunodeficiency virus pseudotyped by murine retroviruses.

Expression of cell surface CD4 influences susceptibility of cells to human immunodeficiency virus (HIV) infection; however, some CD4-positive human and mouse cells are still resistant to HIV infection. To search for mechanisms of resistance to HIV independent of CD4 expression, HIV expression was studied in human and mouse cells normally resistant to HIV infection by introducing infectious virus by transfection of HIV DNA or infection with HIV pseudotyped with amphotropic or polytropic murine leukemia viruses. The results indicated that even when barriers to viral entry were bypassed, mouse NIH 3T3 cells and Dunni cells still showed a marked reduction in number of cells expressing HIV compared with the human cells studied, although the intensity of immunostaining of individual positive mouse cells was indistinguishable from that seen on permissive human cell lines. CD4 expression in mouse cells or human brain or skin cells did not influence the number of HIV foci observed after transfection with HIV DNA or infection with pseudotyped HIV. These results suggested that in addition to a block in the usual HIV fusion and entry process, CD4-positive mouse cells differed from human cells in exhibiting partial resistance to HIV infection which acted at a postpenetration step in the infection cycle. This resistance was partially overcome when mouse cells were infected by direct exposure to human lymphocytes producing HIV pseudotyped by amphotropic murine leukemia virus.     

Neisseria gonorrhoeae enhances infection of dendritic cells by HIV type 1

Clinical studies indicate that Neisseria gonorrhoeae (gonococci (GC)) has the capacity to enhance HIV type 1 (HIV-1) infection. We studied whether GC enhances HIV infection of activated dendritic cells (DCs). The results show that GC can dramatically enhance HIV replication in human DCs during coinfection. The GC component responsible for HIV infection enhancement may be peptidoglycan, which activates TLR2. TLR2 involvement is suggested by bacterial lipoprotein, a TLR2-specific inducer, which stimulates a strong enhancement of HIV infection by human DCs. Moreover, participation of TLR2 is further implicated because GC is unable to stimulate expression of HIV in DCs of TLR2-deficient HIV-1-transgenic mice. These results provide one potential mechanism through which GC infection increases HIV replication in patients infected with both GC and HIV.     

Infection of granulocyte/monocyte progenitor cells with HIV1

In order to study whether cytopathic HIV1 infection of haemopoietic progenitor cells is involved in the derangement of haemopoiesis in patients with HIV1 infection, we infected enriched progenitor cells with HIV1, by addition of viral inoculate supernatants from HIV1-infected peripheral blood mononuclear cells or by coculture with HIV1-infected monocytes/macrophages. Progenitor cells were seeded into colony assays and single colonies were chosen for HIV1 mRNA determination by in situ hybridization. Growth of progenitors was not affected by infection. However, up to 42% of colonies of pluripotent progenitor cells (colony-forming unit/granulocyte-erythrocyte-monocyte; CFU-GEM) and committed progenitor cells CFU/granulocyte-monocyte (CFM-GM) contained HIV1 mRNA-expressing cells.In addition, we studied HIV1 infection of progenitor cells from the bone marrow of 6 patients with AIDS or AIDS-related complex. Two patients were negative, two had a few colonies expressing HIV1 mRNA in a minority of cells, and in the remaining two, up to 11% of CFU-GM contained HIV1-expressing cells.Thus, infection of progenitor cells with HIV1 was achieved experimentally in vitro and occurs in vivo. However, growth of progenitors after in vitro infection continues and therefore HIV1 infection does not seem to contribute directly to the reduced incidence of haemopoietic progenitor cells in vivo.     

The breakdown of the cytokine network subsequent to human immunodeficiency virus infection

The acquired immunodeflciency syndrome (AIDS) is a clinically multifaceted disease induced by infection with the human immunodeficiency virus (HIV). HIV infection results in a complex pattern of immunologic alterations that leads to the development of AIDS in the majority of HIV seropositive (HIV+) individuals. The reduction in CD4 T lymphocyte counts is the hallmark of HIV infection; nevertheless, long before the reduction in CD4 counts reaches critical levels, a series of profound and complex defects that impair the function of CD4 T lymphocytes can be detected. Thus, HIV infection is characterized by quantitative and qualitative defects affecting CD4 T lymphocytes. It was suggested recently that programmed cell death (PCD) is an important mechanism leading to CD4 depletion in HIV infection, and that susceptibility of peripheral lymphocytes to PCD is differentially regulated by diverse cytokines. Thus, type 1 cytokines would protect CD4 lymphocytes against PCD, whereas type 2 cytokines would not protect against, and could augment, PCD. We suggest that the qualitative alterations of the immune response provoke the CD4 depletion characteristic of HIV disease via type 2 cytokinemediated augmentation of PCD, and are therefore ultimately responsible for the progression of HIV infection. Finally, we summarize recent data showing that three correlates of disease progression: emergence of HIV strains with syncitium-inducing ability (SI), type 1-to-type 2 cytokine shift, and CD4 depletion, are significantly associated, suggesting a complex interconnected virologic-immunologic pathogenesis of HIV infection.     

Tuberculosis in patients with human immunodeficiency virus infection. Review of current concepts.

Tuberculosis is a frequent complication of human immunodeficiency virus (HIV)-induced immunosuppression. The diagnosis of extrapulmonary tuberculosis in patients with evidence of HIV infection qualifies as a criterion of the acquired immunodeficiency syndrome. Demographic characteristics of patients with tuberculosis and HIV infection vary by region and reflect the degree to which patients with Mycobacterium tuberculosis infection adopt behaviors that put them at risk for HIV infection. The clinical features of tuberculosis in patients with HIV infection are atypical. Extrapulmonary disease, tuberculin anergy, and unusual findings on chest radiographs occur most frequently when tuberculosis afflicts patients with other clinical evidence of HIV infection at the time tuberculosis is diagnosed. Treatment is effective for tuberculosis in HIV-seropositive patients, and isoniazid prophylaxis is recommended for HIV-infected patients with positive tuberculin skin tests.     

Semen protects CD4+ target cells from HIV infection but promotes the preferential transmission of R5 tropic HIV

Sexual intercourse is the major means of HIV transmission, yet the impact of semen on HIV infection of CD4(+) T cells remains unclear. To resolve this conundrum, we measured CD4(+) target cell infection with X4 tropic HIV IIIB and HC4 and R5 tropic HIV BaL and SF162 after incubation with centrifuged seminal plasma (SP) from HIV-negative donors and assessed the impact of SP on critical determinants of target cell susceptibility to HIV infection. We found that SP potently protects CD4(+) T cells from infection with X4 and R5 tropic HIV in a dose- and time-dependent manner. SP caused a diminution in CD4(+) T cell surface expression of the HIVR CD4 and enhanced surface expression of the HIV coreceptor CCR5. Consequently, SP protected CD4(+) T cells from infection with R5 tropic HIV less potently than it protected CD4(+) T cells from infection with X4 tropic HIV. SP also reduced CD4(+) T cell activation and proliferation, and the magnitude of SP-mediated suppression of target cell CD4 expression, activation, and proliferation correlated closely with the magnitude of the protection of CD4(+) T cells from infection with HIV. Taken together, these data show that semen protects CD4(+) T cells from HIV infection by restricting critical determinants of CD4(+) target cell susceptibility to HIV infection. Further, semen contributes to the selective transmission of R5 tropic HIV to CD4(+) target cells.     

Comparative analysis of the serum microbiome of HIV infected individuals

HIV infects the CD4 cells which marks the suppression of our immune system. DNA from serum of healthy, treated and untreated HIV infected individuals was extracted. The DNA was subjected to 16S metagenomic sequencing and analyzed using QIIME2 pipeline. 16S sequencing analysis showed serum microbiome was dominated by Firmicutes, Proteobacteria, Bacteroidota and Actinobacteria. Treated HIV infection showed highest abundance of Firmicutes (66.40%) significantly higher than untreated HIV infection (35.88%) and control (41.89%). Bacilli was most abundant class in treated (63.59%) and second most abundant in untreated (34.53%) while control group showed highest abundance of class Gamma-proteobacteria (45.86%). Untreated HIV infection group showed Enterococcus (10.72%) and Streptococcus (6.599%) as the most abundant species. Untreated HIV infection showed significantly higher (p = 0.0039) species richness than treated and control groups. An altered serum microbiome of treated HIV infection and higher microbial abundance in serum of untreated HIV infection was observed.     

Parameters of human immunodeficiency virus infection of human cervical tissue and inhibition by vaginal virucides

Heterosexual transmission of human immunodeficiency virus (HIV) is the most frequent mode of infection worldwide. However, the immediate events between exposure to infectious virus and establishment of infection are still poorly understood. This study investigates parameters of HIV infection of human female genital tissue in vitro using an explant culture model. In particular, we investigated the role of the epithelium and virucidal agents in protection against HIV infection. We have demonstrated that the major target cells of infection reside below the genital epithelium, and thus HIV must cross this barrier to establish infection. Immune activation enhanced HIV infection of such subepithelial cells. Furthermore, our data suggest that genital epithelial cells were not susceptible to HIV infection, appear to play no part in the transfer of infectious virus across the epithelium, and thus may provide a barrier to infection. In addition, experiments using a panel of virucidal agents demonstrated differential efficiency to block HIV infection of subepithelial cells from partial to complete inhibition. This is the first demonstration that virucidal agents designed for topical vaginal use block HIV infection of genital tissue. Such agents have major implications for world health, as they will provide women with a mechanism of personal and covert protection from HIV infection.     

Disruption of Type I Interferon Induction by HIV Infection of T Cells

Our main objective of this study was to determine how Human Immunodeficiency Virus (HIV) avoids induction of the antiviral Type I Interferon (IFN) system. To limit viral infection, the innate immune system produces important antiviral cytokines such as the IFN. IFN set up a critical roadblock to virus infection by limiting further replication of a virus. Usually, IFN production is induced by the recognition of viral nucleic acids by innate immune receptors and subsequent downstream signaling. However, the importance of IFN in the defense against viruses has lead most pathogenic viruses to evolve strategies to inhibit host IFN induction or responses allowing for increased pathogenicity and persistence of the virus. While the adaptive immune responses to HIV infection have been extensively studied, less is known about the balance between induction and inhibition of innate immune defenses, including the antiviral IFN response, by HIV infection. Here we show that HIV infection of T cells does not induce significant IFN production even IFN I Interferon production. To explain this paradox, we screened HIV proteins and found that two HIV encoded proteins, Vpu and Nef, strongly antagonize IFN induction, with expression of these proteins leading to loss of expression of the innate immune viral RNA sensing adaptor protein, IPS-1 (IFN-β promoter stimulator-1). We hypothesize that with lower levels of IPS-1 present, infected cells are defective in mounting antiviral responses allowing HIV to replicate without the normal antiviral actions of the host IFN response. Using cell lines as well as primary human derived cells, we show that HIV targeting of IPS-1 is key to limiting IFN induction. These findings describe how HIV infection modulates IFN induction providing insight into the mechanisms by which HIV establishes infection and persistence in a host.     

For a better understanding of the mechanisms involved in vertical transmission of HIV

Maternal-infant transmission of human immunodeficiency virus-1 (HIV) is the primary cause of this retrovirus infection in neonates. The mechanisms of vertical transmission of HIV, in particular in utero transmission, remain poorly defined. Trophoblastic cells from the placenta are thought to be a target of HIV infection and/or may be utilized by the virus to be transported across the placental barrier by a process known as transcytosis. The vertical transmission of HIV (via infection or transcytosis) may be either favoured or inhibited by factors related to both the viral phenotype and the cellular environment.     

The characteristics of the course of tuberculosis in HIV-infected patients and prophylactic measures

Morbidity in HIV infection and tuberculosis in persons having these two infections in association was analyzed. According to the data for the end of the first quarter of 1997 the presence of association of HIV infection with tuberculosis was found in 91 patients. In 70.3% of cases HIV infection was contacted before the appearance of tuberculosis and in 18.7% of cases, after it; in 11% of cases the order of appearance of these two diseases could not be established. The study revealed that the markedness of the clinical picture of tuberculosis was determined by the progress of HIV infection.     

Altering cell death pathways as an approach to cure HIV infection

Recent cases of successful control of human immunodeficiency virus (HIV) by bone marrow transplant in combination with suppressive antiretroviral therapy (ART) and very early initiation of ART have provided proof of concept that HIV infection might now be cured. Current efforts focusing on gene therapy, boosting HIV-specific immunity, reducing inflammation and activation of latency have all been the subject of recent excellent reviews. We now propose an additional avenue of research towards a cure for HIV: targeting HIV apoptosis regulatory pathways. The central enigma of HIV disease is that HIV infection kills most of the CD4 T cells that it infects, but those cells that are spared subsequently become a latent reservoir for HIV against which current medications are ineffective. We propose that if strategies could be devised which would favor the death of all cells which HIV infects, or if all latently infected cells that release HIV would succumb to viral-induced cytotoxicity, then these approaches combined with effective ART to prevent spreading infection, would together result in a cure for HIV. This premise is supported by observations in other viral systems where the relationship between productive infection, apoptosis resistance, and the development of latency or persistence has been established. Therefore we propose that research focused at understanding the mechanisms by which HIV induces apoptosis of infected cells, and ways that some cells escape the pro-apoptotic effects of productive HIV infection are critical to devising novel and rational approaches to cure HIV infection.     

Differential effects of migration and deportation on HIV infection among male and female injection drug users in Tijuana, Mexico

HIV prevalence is rising, especially among high risk females in Tijuana, Baja California, a Mexico-US border city situated on major migration and drug trafficking routes. We compared factors associated with HIV infection among male and female injection drug users (IDUs) in Tijuana in an effort to inform HIV prevention and treatment programs. IDUs aged > or = 18 years were recruited using respondent-driven sampling and underwent testing for HIV, syphilis and structured interviews. Logistic regression identified correlates of HIV infection, stratified by gender. Among 1056 IDUs, most were Mexican-born but 67% were born outside Tijuana. Reasons for moving to Tijuana included deportation from the US (56% for males, 29% for females), and looking for work/better life (34% for females, 15% for males). HIV prevalence was higher in females versus males (10.2% vs. 3.5%, p = 0.001). Among females (N = 158), factors independently associated with higher HIV prevalence included younger age, lifetime syphilis infection and living in Tijuana for longer durations. Among males (N = 898), factors independently associated with higher HIV prevalence were syphilis titers consistent with active infection, being arrested for having 'track-marks', having larger numbers of recent injection partners and living in Tijuana for shorter durations. An interaction between gender and number of years lived in Tijuana regressed on HIV infection was significant (p = 0.03). Upon further analysis, deportation from the U.S. explained the association between shorter duration lived in Tijuana and HIV infection among males; odds of HIV infection were four-fold higher among male injectors deported from the US, compared to other males, adjusting for all other significant correlates (p = 0.002). Geographic mobility has a profound influence on Tijuana's evolving HIV epidemic, and its impact is significantly modified by gender. Future studies are needed to elucidate the context of mobility and HIV acquisition in this region, and whether US immigration policies adversely affect HIV risk.     

Infection of dendritic cells (DCs), not DC-SIGN-mediated internalization of human immunodeficiency virus, is required for long-term transfer of virus to T cells

The C-type lectin DC-SIGN expressed on immature dendritic cells (DCs) captures human immunodeficiency virus (HIV) particles and enhances the infection of CD4+ T cells. This process, known as trans-enhancement of T-cell infection, has been related to HIV endocytosis. It has been proposed that DC-SIGN targets HIV to a nondegradative compartment within DCs and DC-SIGN-expressing cells, allowing incoming virus to persist for several days before infecting target cells. In this study, we provide several lines of evidence suggesting that intracellular storage of intact virions does not contribute to HIV transmission. We show that endocytosis-defective DC-SIGN molecules enhance T-cell infection as efficiently as their wild-type counterparts, indicating that DC-SIGN-mediated HIV internalization is dispensable for trans-enhancement. Furthermore, using immature DCs that are genetically resistant to infection, we demonstrate that several days after viral uptake, HIV transfer from DCs to T cells requires viral fusion and occurs exclusively through DC infection and transmission of newly synthesized viral particles. Importantly, our results suggest that DC-SIGN participates in this process by cooperating with the HIV entry receptors to facilitate cis-infection of immature DCs and subsequent viral transfer to T cells. We suggest that such a mechanism, rather than intracellular storage of incoming virus, accounts for the long-term transfer of HIV to CD4+ T cells and may contribute to the spread of infection by DCs.     

Laboratory diagnostics of HIV infection in Syberian federal district

Spread of HIV infection in the Russian Federation is an important problem of the state healthcare. Data on HIV infection diagnostics in the Syberian federal district in 2005-2009 are presented. Coverage of population by HIV examination, rate of positive study results by enzyme immunoassay and rate of positive EIA confirmed by immunoblotting are presented.     

Relative inefficiency of soluble recombinant CD4 for inhibition of infection by monocyte-tropic HIV in monocytes and T cells

Macrophages are major viral reservoirs in the brain, lungs, and lymph nodes of HIV-infected patients. But not all HIV isolates infect macrophages. The molecular basis for this restrictive target cell tropism and the mechanisms by which HIV infects macrophages are not well understood: virus uptake by CD4-dependent and -independent pathways have both been proposed. Soluble rCD4 (sCD4) binds with high affinity to gp 120, the envelope glycoprotein of HIV, and at relatively low concentrations (less than 1 microgram/ml) completely inhibits infection of many HIV strains in T cells or T cell lines. HTLV-IIIB infection of the H9 T cell line was completely inhibited by prior treatment of virus with 10 micrograms/ml sCD4: no p24 Ag or HIV-induced T cell syncytia were detected in cultures of H9 cells exposed to 1 x 10(4) TCID50 HTLV-IIIB in the presence of sCD4. Under identical conditions and at a 100-fold lower viral inoculum, 10 micrograms/ml sCD4 had little or no effect on infection of monocytes by any of six different HIV isolates by three different criteria: p24 Ag release, virus-induced cytopathic effects, and the frequency of infected cells that express HIV-specific mRNA. At 10- to 100-fold higher concentrations of sCD4, however, infection was completely inhibited. Monoclonal anti-CD4 also prevented infection of these same viral isolates in monocytes. The relative inefficiency of sCD4 for inhibition of HIV infection in monocytes was a property of the virion, not the target cell: HIV isolates that infect both monocytes and T cells required similarly high levels of sCD4 (100 to 200 micrograms/ml) for inhibition of infection. These data suggest that the gp120 of progeny HIV derived from macrophages interacts with sCD4 differently than that of virions derived from T cells. For both variants of HIV, however, the predominant mechanism of virus entry for infection is CD4-dependent.     

Impact of HIV infection on mortality in young men in a London health authority.

OBJECTIVE--To determine the number of deaths attributable to HIV infection among men aged 15-64 in a geographically defined population in the United Kingdom. DESIGN--Retrospective review of death certificates and linkage with local and national HIV and AIDS surveillance data. SETTING--Riverside District Health Authority, London. MAIN OUTCOME MEASURES--Numbers of deaths attributed to HIV infection in male residents of Riverside aged 15-64 and 15-44 over a six month period. Proportion of attributed deaths were (i) identified from death certificates by the Office of Population Censuses and Surveys as being due to HIV infection and (ii) reported as cases of AIDS or HIV related deaths to the Public Health Laboratory Service Communicable Disease Surveillance Centre. RESULTS--34 of 213 (16%) deaths in men aged 15-64 and 27 of 69 (39%) deaths in men aged 15-44 were attributed to HIV infection. Six of 33 (18%) attributed deaths were identified by the Office of Population Censuses and Surveys and 32/34 (94%) were reported to the Communicable Disease Surveillance Centre. CONCLUSIONS--HIV infection was the leading cause of death in male residents of Riverside aged 15-44 and the third commonest cause of death in those aged 15-64. Most individuals dying of known HIV infection were reported to the Communicable Disease Surveillance Centre but identification of the true cause of death from the process of death certification was poor. Measures to improve the certification of HIV and AIDS or the use of AIDS surveillance information correctly to code the cause of death needs to be considered to ensure that the true impact of HIV infection is reflected in routine mortality statistics.     

The usefulness of defined clinical features in the diagnosis of HIV/AIDS infection in Sierra Leone.

Sierra Leone ranks at the bottom of the global World Bank Development Index based on multiple health and economic indices and lacks the resources to purchase HIV diagnostic kits. Our study has defined some common clinical features presenting HIV infection that could form clinical algorithms for the diagnosis and recognition of HIV infection by health workers in Sierra Leone. In a private clinic in Freetown, Sierra Leone, West Africa, 106 out of a total of 124 patients presenting with various symptoms and strong clinical suspicion of HIV infection within a two-year period (1999 and 2000), were deemed positive by two different ELISA tests. The prevalence of HIV infection seen in this private clinic in Freetown in 2000 was 14.89% as compared to 9.25% in 1999. The positive predictive value of our clinical diagnosis of HIV/AIDS infection was 85.5%. The male:female ratio of the patients in our series was 1:1.9, with a mean age of 39 years for males and 28 years for females. HIV infection was found in a cross-section of the population that we examined. Heterosexual contact appeared to be the major mode of transmission amongst our patients and there seemed to be a significant epidemiological risk of HIV infection amongst those who traveled to other countries in the West African sub region. Common clinical features in decreasing frequency were fever (92.5%), weight loss (84.1%), lymphadenopathy (78.3%), cough (48.1%), diarrhea (37.7%), candidiasis (32.1%) and body aches (30.1%).     

Automated genome-wide visual profiling of cellular proteins involved in HIV infection

Recent genome-wide RNAi screens have identified >842 human genes that affect the human immunodeficiency virus (HIV) cycle. The list of genes implicated in infection differs between screens, and there is minimal overlap. A reason for this variance is the interdependence of HIV infection and host cell function, producing a multitude of indirect or pleiotropic cellular effects affecting the viral infection during RNAi screening. To overcome this, the authors devised a 15-dimensional phenotypic profile to define the viral infection block induced by CD4 silencing in HeLa cells. They demonstrate that this phenotypic profile excludes nonspecific, RNAi-based side effects and viral replication defects mediated by silencing of housekeeping genes. To achieve statistical robustness, the authors used automatically annotated RNAi arrays for seven independent genome-wide RNAi screens. This identified 56 host genes, which reliably reproduced CD4-like phenotypes upon HIV infection. The factors include 11 known HIV interactors and 45 factors previously not associated with HIV infection. As proof of concept, the authors confirmed that silencing of PAK1, Ku70, and RNAseH2A impaired HIV replication in Jurkat cells. In summary, multidimensional, visual profiling can identify genes required for HIV infection.     

siRNA screening of a targeted library of DNA repair factors in HIV infection reveals a role for base excision repair in HIV integration

Host DNA repair enzymes have long been assumed to play a role in HIV replication, and many different DNA repair factors have been associated with HIV. In order to identify DNA repair pathways required for HIV infection, we conducted a targeted siRNA screen using 232 siRNA pools for genes associated with DNA repair. Mapping the genes targeted by effective siRNA pools to well-defined DNA repair pathways revealed that many of the siRNAs targeting enzymes associated with the short patch base excision repair (BER) pathway reduced HIV infection. For six siRNA pools targeting BER enzymes, the negative effect of mRNA knockdown was rescued by expression of the corresponding cDNA, validating the importance of the gene in HIV replication. Additionally, mouse embryo fibroblasts (MEFs) lacking expression of specific BER enzymes had decreased transduction by HIV-based retroviral vectors. Examining the role BER enzymes play in HIV infection suggests a role for the BER pathway in HIV integration.