Vertical human immunodeficiency virus type 1 - HIV-1 -transmission - a review

Several factors appear to affect vertical HIV-1 transmission, dependent mainly on characteristics of the mother (extent of immunodeficiency, co-infections, risk behaviour, nutritional status, immune response, genetical make-up), but also of the virus (phenotype, tropism) and, possibly, of the child (genetical make-up). This complex situation is compounded by the fact that the virus may have the whole gestation period, apart from variable periods between membrane rupture and birth and the breast-feeding period, to pass from the mother to the infant. It seems probable that an extensive interplay of all factors occurs, and that some factors may be more important during specific periods and other factors in other periods. Factors predominant in protection against in utero transmission may be less important for peri-natal transmission, and probably quite different from those that predominantly affect transmission by mothers milk. For instance, cytotoxic T lymphocytes will probably be unable to exert any effect during breast-feeding, while neutralizing antibodies will be unable to protect transmission by HIV transmitted through infected cells. Furthermore, some responses may be capable of controlling transmission of determined virus types, while being inadequate for controlling others. As occurence of mixed infections and recombination of HIV-1 types is a known fact, it does not appear possible to prevent vertical HIV-1 transmission by reinforcing just one of the factors, and probably a general strategy including all known factors must be used. Recent reports have brought information on vertical HIV-1 transmission in a variety of research fields, which will have to be considered in conjunction as background for specific studies.

HIV-1 Polymorphism: a Challenge for Vaccine Development - A Review

The perspective for the development of anti-HIV/AIDS vaccines became a target sought by several research groups and pharmaceutical companies. However, the complex virus biology in addition to a striking genetic variability and the limited understanding of the immunological correlates of protection have made this an enormous scientific challenge not overcome so far. In this review we presented an updating of HIV-1 subtypes and recombinant viruses circulating in South American countries, focusing mainly on Brazil, as one of the challenges for HIV vaccine development. Moreover, we discussed the importance of stimulating developing countries to participate in the process of vaccine evaluation, not only testing vaccines according to already defined protocols, but also working together with them, in order to take into consideration their local information on virus diversity and host genetic background relevant for the vaccine development and testing, as well as including local virus based reagents to evaluate the immunogenicity of the candidate vaccines.

Improved immunogenicity against HIV-1 clade C antigens by using NYVAC-C with restored replication competence

Background: In order to improve the immunogenicity of currently available non-replicating pox virus HIV vaccine vectors, NYVAC was genetically modified through re-insertion of two host range genes (K1L and C7L), resulting in restored replicative capacity in human cells. Methods: In the present study these vectors, expressing either a combination of the HIV-1 clade C antigens Env, Gag, Pol, Nef, or a combination of Gal, Pol, Nef were evaluated for safety and immunogenicity in rhesus macaques, which were immunized at weeks 0, 4 and 12 either by scarification (conventional poxvirus route of immunization), intradermal or by intramuscular injection (route used in previous vaccine studies). Results: Replication competent NYVAC-C-KC vectors induced higher HIV-specific responses, as measured by IFN-g ELISpot assay, than the replication defective NYVAC-C vectors. Application through scarification only required one immunization to induce maximum HIV-specific immune responses. This method simultaneously induced relatively lower anti-vector responses. In contrast, two to three immunizations were required when the NYVAC-C-KC vectors were given by intradermal or intramuscular injection and this method tended to generate slightly lower responses. Responses were predominantly directed against Env in the animals that received NYVAC-C-KC vectors expressing HIV-1 Env, Gag, Pol, Nef, while Gag responses were dominant in the NYVAC-C-KC HIV-1 Gag, Pol, Nef immunized animals. Conclusion: The current study demonstrates that NYVAC replication competent vectors were well tolerated and showed increased immunogenicity as compared to replication defective vectors. Further studies are needed to evaluate the most efficient route of immunization and to explore the use of these replication competent NYVAC vectors in prime/boost combination with gp120 proteinbased vaccine candidates. This study was performed within the Poxvirus T-cell Vaccine Discovery Consortium (PTVDC) which is part of the CAVD program.

Systemic antibody responses to gut commensal bacteria during chronic HIV-1 infection.

BACKGROUND: Human systemic antibody responses to commensal microbiota are not well characterised during health and disease. Of particular interest is the analysis of their potential modulation caused by chronic HIV-1 infection which is associated with sustained enteropathy and systemic B cell disturbances reflected by impaired B cell responses and chronic B cell hyperactivity. The mechanisms underlying B cell hyperactivation and the specificities of the resulting hypergammaglobulinaemia are only poorly understood. METHODS: By a technique referred to as live bacterial FACS (fluorescence-activated cell sorting), the present study investigated systemic antibody responses to several gut and skin commensal bacteria as well as Candida albicans in longitudinal plasma and serum samples from healthy donors, chronic HIV-1-infected individuals with or without diarrhoea and patients with inflammatory bowel disease (IBD). RESULTS: The data show that systemic antibody responses to the commensal microbiota were abundantly present in humans and remained remarkably stable over years. Overall systemic antibody responses to gut commensal bacteria were not affected during chronic HIV-1 infection, with titres decreasing when normalised to elevated plasma immunoglobulin G (IgG) levels found in patients with HIV. In contrast, increases in the titres of high affinity antimicrobiota antibodies were detected in patients with IBD, demonstrating that conditions with known increased intestinal permeability and aberrant mutualism can induce changes in antibody titres observed in these assays. CONCLUSION: Neither HIV-associated enteropathy nor B cell dysfunction impact on the high-affinity systemic antibody responses to gut commensal bacteria. HIV-associated hypergammaglobulinaemia is therefore unlikely to be driven by induction of antimicrobiota antibodies.

Effectiveness and safety of isoniazid chemoprophylaxis for HIV-1 infected patients from Rio de Janeiro

The clinical and epidemiological characteristics, adverse events, treatment adherence and effectiveness of isoniazid chemoprophylaxis were analyzed in a cohort of 138 tuberculosis/HIV-coinfected patients. An open, non-randomized, pragmatic prophylactic trial was conducted on adult patients with a normal chest X-ray and positive tuberculin skin test (> 5 mm) who received isoniazid chemoprophylaxis (300 mg/day) for six months. The mean of follow up was 2.8 years (SD 1.3). Adherence to chemoprophylaxis was 87.7% (121/138). Only one patient presented tuberculosis after the end of chemoprophylaxis, corresponding to 0.3 cases per 100 persons per year. The relative risk of some adverse effects was 4.6 times higher (95% CI: 1.9-11.5) in patients with positive anti-HCV serology (4/9, 44.4%) compared to those with negative serology (12/129, 9.6%) (p = 0.002). This study provides evidence regarding the effectiveness and safety of a short and self-administered isoniazid regimen. We recommend the implementation of this routine by health service practitioners.

Assessment of recent HIV-1 infection by a line immunoassay for HIV-1/2 confirmation.

BACKGROUND: Knowledge of the number of recent HIV infections is important for epidemiologic surveillance. Over the past decade approaches have been developed to estimate this number by testing HIV-seropositive specimens with assays that discriminate the lower concentration and avidity of HIV antibodies in early infection. We have investigated whether this "recency" information can also be gained from an HIV confirmatory assay. METHODS AND FINDINGS: The ability of a line immunoassay (INNO-LIA HIV I/II Score, Innogenetics) to distinguish recent from older HIV-1 infection was evaluated in comparison with the Calypte HIV-1 BED Incidence enzyme immunoassay (BED-EIA). Both tests were conducted prospectively in all HIV infections newly diagnosed in Switzerland from July 2005 to June 2006. Clinical and laboratory information indicative of recent or older infection was obtained from physicians at the time of HIV diagnosis and used as the reference standard. BED-EIA and various recency algorithms utilizing the antibody reaction to INNO-LIA's five HIV-1 antigen bands were evaluated by logistic regression analysis. A total of 765 HIV-1 infections, 748 (97.8%) with complete test results, were newly diagnosed during the study. A negative or indeterminate HIV antibody assay at diagnosis, symptoms of primary HIV infection, or a negative HIV test during the past 12 mo classified 195 infections (26.1%) as recent (< or = 12 mo). Symptoms of CDC stages B or C classified 161 infections as older (21.5%), and 392 patients with no symptoms remained unclassified. BED-EIA ruled 65% of the 195 recent infections as recent and 80% of the 161 older infections as older. Two INNO-LIA algorithms showed 50% and 40% sensitivity combined with 95% and 99% specificity, respectively. Estimation of recent infection in the entire study population, based on actual results of the three tests and adjusted for a test's sensitivity and specificity, yielded 37% for BED-EIA compared to 35% and 33% for the two INNO-LIA algorithms. Window-based estimation with BED-EIA yielded 41% (95% confidence interval 36%-46%). CONCLUSIONS: Recency information can be extracted from INNO-LIA-based confirmatory testing at no additional costs. This method should improve epidemiologic surveillance in countries that routinely use INNO-LIA for HIV confirmation.

Molecular epidemiology of HIV-1 clades in Southern Brazil

Human immunodeficiency virus (HIV) clades B and C account for more than 60% of the HIV-1 infections worldwide. In this paper, we describe the profiles of patients infected with subtypes of HIV-1 from the state of Paraná, Southern Brazil, and correlate them with demographic and epidemiological findings. A retrospective analysis of HIV cases reported from 1999-2007 was also performed. Data from 293 patients were reviewed and 245 were older than 13 (58% female). The distribution of clades was as follows: B 140 (57%), C 67 (23%), F 24 (10%) and mosaic or unique recombinant forms (URFs) 24 (10%). Of the 48 patients younger than 13 years of age (62.5% male), vertical transmission occurred in 46 and the distribution of clades was as follows: B 14 (29%), C 24 (50%), F 7 (15%) and URFs 6 (13%). There was no significant difference in mortality between HIV-1 subtypes. In both groups, patients infected with clade C tended to have higher rates of injection drug use exposure risk.

The impact of the nelfinavir resistance-conferring mutation D30N on the susceptibility of HIV-1 subtype B to other protease inhibitors

The human immunodeficiency virus type 1 (HIV-1) protease mutation D30N is exclusively selected by the protease inhibitor (PI) nelfinavir and confers resistance to this drug. We demonstrate that D30N increases the susceptibility to saquinavir (SQV) and amprenavir in HIV-1 subtype B isolates and that the N88D mutation in a D30N background neutralizes this effect. D30N also suppresses indinavir (IDV) resistance caused by the M46I mutation. Interestingly, in patients with viruses originally containing the D30N mutation who were treated with IDV or SQV, the virus either reversed this mutation or acquired N88D, suggesting an antagonistic effect of D30N upon exposure to these PIs. These findings can improve direct salvage drug treatment in resource limited countries where subtype B is epidemiologically important and extend the value of first and second line PIs in these populations.

The effect of combined polymorphisms in chemokines and chemokine receptors on the clinical course of HIV-1 infection in a Brazilian population

Polymorphisms in genes that encode chemokines or their receptors can modulate susceptibility to human immunodeficiency virus (HIV) infection and disease progression. The objective of this study was to assess the frequency of polymorphisms CCR5-Δ32, CCR2-64I, CCR5-59029A and SDF1-3'A and their role in the course of HIV infection in a Southern Brazilian population. Clinical data were obtained from 249 patients for an average period of 6.4 years and genotypes were determined by standard polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism. Survival analyses were conducted for three outcomes: CD4+ T-cell counts below 200 cells/µL, acquired immune deficiency syndrome (AIDS) or death. The frequency of the polymorphisms CCR5-Δ32, CCR2-64I, CCR5-59029A and SDF1-3'A were 0.024, 0.113, 0.487 and 0.207, respectively. CCR5-Δ32 was associated with a reduction in the risk for CD4+ T-cell depletion and with an increased risk for death after AIDS diagnosis. CCR2-64I was associated with a reduction in the risk for developing AIDS. SDF1-3'A was also associated with decreased risk for AIDS, but its effect was only evident when CCR2-64I was present as well. These results highlight the possibility of using these markers as indicators for the prognosis of disease progression and provide evidence for the importance of analysing the effects of gene polymorphisms in a combined fashion.

Factors associated with the emergence of K65R in patients with HIV-1 infection treated with combination antiretroviral therapy containing tenofovir.

BACKGROUND: The human immunodeficiency virus type 1 reverse-transcriptase mutation K65R is a single-point mutation that has become more frequent after increased use of tenofovir disoproxil fumarate (TDF). We aimed to identify predictors for the emergence of K65R, using clinical data and genotypic resistance tests from the Swiss HIV Cohort Study. METHODS: A total of 222 patients with genotypic resistance tests performed while receiving treatment with TDF-containing regimens were stratified by detectability of K65R (K65R group, 42 patients; undetected K65R group, 180 patients). Patient characteristics at start of that treatment were analyzed. RESULTS: In an adjusted logistic regression, TDF treatment with nonnucleoside reverse-transcriptase inhibitors and/or didanosine was associated with the emergence of K65R, whereas the presence of any of the thymidine analogue mutations D67N, K70R, T215F, or K219E/Q was protective. The previously undescribed mutational pattern K65R/G190S/Y181C was observed in 6 of 21 patients treated with efavirenz and TDF. Salvage therapy after TDF treatment was started for 36 patients with K65R and for 118 patients from the wild-type group. Proportions of patients attaining human immunodeficiency virus type 1 loads <50 copies/mL after 24 weeks of continuous treatment were similar for the K65R group (44.1%; 95% confidence interval, 27.2%-62.1%) and the wild-type group (51.9%; 95% confidence interval, 42.0%-61.6%). CONCLUSIONS: In settings where thymidine analogue mutations are less likely to be present, such as at start of first-line therapy or after extended treatment interruptions, combinations of TDF with other K65R-inducing components or with efavirenz or nevirapine may carry an enhanced risk of the emergence of K65R. The finding of a distinct mutational pattern selected by treatment with TDF and efavirenz suggests a potential fitness interaction between K65R and nonnucleoside reverse-transcriptase inhibitor-induced mutations.

An evaluation of p16INK4a expression in cervical intraepithelial neoplasia specimens, including women with HIV-1

Although several studies have evaluated the role of p16INK4a as a diagnostic marker of cervical intraepithelial neoplasia (CIN) and its association with disease progression, studies regarding the role of p16INK4a in human immunodeficiency virus (HIV)-infected patients remain scarce. The present study was designed to determine the potential utility of p16INK4a as a diagnostic marker for CIN and invasive cervical cancer in HIV-positive and negative cervical specimens. An immunohistochemical analysis of p16INK4a was performed in 326 cervical tissue microarray specimens. Performance indicators were calculated and compared using receiving operating characteristics curve (ROC)/area under the curve. In HIV-1-negative women, the percentage of cells that was positive for p16INK4a expression was significantly correlated with the severity of CIN (p < 0.0001). A ROC curve with a cut-off value of 55.28% resulted in a sensitivity of 89%, a specificity of 81%, a positive predictive value of 91% and a negative predictive value of 78%. HIV-seropositive women exhibited decreased expression of p16INK4a in CIN2-3 specimens compared with HIV-negative specimens (p = 0.031). The ROC data underscore the potential utility of p16INK4a under defined conditions as a diagnostic marker for CIN 2-3 staging and invasive cervical cancer. HIV-1 infection, however, is associated with relatively reduced p16INK4a expression in CIN 2-3.

Protection from HIV-1 infection of primary CD4 T cells by CCR5 silencing is effective for the full spectrum of CCR5 expression.

Stable gene silencing by RNA interference (RNAi) can be achieved by expression of small hairpin RNAs (shRNAs) from RNA polymerase III promoters. We have tested lentiviral vectors expressing shRNAs targetting CCR5 in primary CD4 T cells from donors representing various CCR5 and CCR2 genetic backgrounds covering the full spectrum of CCR5 expression levels and permissiveness for HIV-1 infection. A linear decrease in CCR5 expression resulted in a logarithmic decrease in cellular infection, giving up to three logs protection from HIV-1 infection in vitro. Protection was maintained at very high multiplicity of infection. This and other recent reports on RNAi should open a debate about the use of RNAi gene therapy for HIV infection.

Social meets molecular: Combining phylogenetic and latent class analyses to understand HIV-1 transmission in Switzerland.

Switzerland has a complex human immunodeficiency virus (HIV) epidemic involving several populations. We examined transmission of HIV type 1 (HIV-1) in a national cohort study. Latent class analysis was used to identify socioeconomic and behavioral groups among 6,027 patients enrolled in the Swiss HIV Cohort Study between 2000 and 2011. Phylogenetic analysis of sequence data, available for 4,013 patients, was used to identify transmission clusters. Concordance between sociobehavioral groups and transmission clusters was assessed in correlation and multiple correspondence analyses. A total of 2,696 patients were infected with subtype B, 203 with subtype C, 196 with subtype A, and 733 with recombinant subtypes (mainly CRF02_AG and CRF01_AE). Latent class analysis identified 8 patient groups. Most transmission clusters of subtype B were shared between groups of gay men (groups 1-3) or between the heterosexual groups "heterosexual people of lower socioeconomic position" (group 4) and "injection drug users" (group 8). Clusters linking homosexual and heterosexual groups were associated with "older heterosexual and gay people on welfare" (group 5). "Migrant women in heterosexual partnerships" (group 6) and "heterosexual migrants on welfare" (group 7) shared non-B clusters with groups 4 and 5. Combining approaches from social and molecular epidemiology can provide insights into HIV-1 transmission and inform the design of prevention strategies.