Potent Antiretroviral Therapy for Human Immunodeficiency Virus Infection Increases Aortic Stiffness

Background: Highly active antiretroviral therapy for AIDS is known to increase cardiovascular risk, but the effects of potent antiretroviral agents according to gender are unknown. Objective: The present study evaluated the impact of HIV infection treatment on aortic stiffness according to gender. Methods: From university-affiliated hospitals, we recruited 28 AIDS patients undergoing highly active antiretroviral treatment (HAART), 28 treatment-naive HIV-infected patients, 44 patients with type 2 diabetes, and 30 controls. Aortic stiffness was determined by measuring pulse wave velocity (PWV) using a validated and non-invasive automatic device. Results: The crude mean PWV values and 95% confidence intervals (95% CI) for HAART, diabetics, and controls were 9.77 m/s (95% CI 9.17-10.36),, 9.00 m/s (95% CI 8.37-9.63), 9.90 m/s (95% CI 9.32-10.49), and 9.28 m/s (95% CI 8.61-9.95), respectively, for men (P-value for trend = 0.14), and 9.61 m/s (95% CI 8.56-10.66), 8.45 m/s (95% CI 7.51-9.39), 9.83 (95% CI 9.21-10.44), and 7.79 m/s (95% CI 6.99-8.58), respectively, for women (P-value for trend <0.001). Post-hoc analysis revealed a significant difference between the mean PWV values in the HAART group and controls in women (P-value <0.01). After adjusting for other potential covariates, including systolic blood pressure and diabetes, these results did not change. The findings indicate that the impact of HAART treatment on aortic stiffness was amplified in women with hypertension, dyslipidemia, and metabolic syndrome. Conclusion: Potent anti-retroviral agents used in the treatment of HIV infection increases aortic stiffness, mainly among women with higher cardiovascular risk. (Arq Bras Cardiol 2012;99(6):1100-1107)

JC virus-associated central nervous system diseases in HIV-infected patients in Brazil: clinical presentations, associated factors with mortality and outcome

Introduction: Several presentations of neurologic complications caused by JC virus (JCV) in human immunodeficiency virus (HIV)-infected patients have been described and need to be distinguished from the "classic" form of progressive multifocal leukoencephalopathy (PML). The objectives of this study were: 1) to describe the spectrum and frequency of presentations of JCV-associated central nervous system (CNS) diseases; 2) identify factors associated with in-hospital mortality of patients with JCV-associated CNS disease; and 3) to estimate the overall mortality of this population. Material and methods: This was a retrospective study of HIV-infected patients admitted consecutively for JCV-associated CNS diseases in a referral teaching center in Sao Paulo, Brazil, from 2002 to 2007. All patients with laboratory confirmed JCV-associated CNS diseases were included using the following criteria: compatible clinical and radiological features associated with the presence of JCV DNA in the cerebrospinal fluid. JCV-associated CNS diseases were classified as follows: 1) classic PML; 2) inflammatory PML; and 3) JC virus granule cell neuronopathy (GCN). Results: We included 47 cases. JCV-associated CNS diseases were classified as follows: 1) classic PML: 42 (89%); 2) inflammatory PML: three (6%); and 3) JC virus GCN: four (9%). Nosocomial pneumonia (p = 0.003), previous diagnosis of HIV infection (p = 0.03), and imaging showing cerebellar and/or brainstem involvement (p = 0.02) were associated with in-hospital mortality. Overall mortality during hospitalization was 34%. Conclusions: Novel presentations of JCV-associated CNS diseases were observed in our setting; nosocomial pneumonia, previous diagnosis of HIV infection, and cerebellar and/or brainstem involvement were associated with in-hospital mortality; and overall mortality was high. (C) 2012 Elsevier Editora Ltda. All rights reserved.

Tax Gene Characterization of Human T-Lymphotropic Virus Type 1 Strains from Brazilian HIV-Coinfected Patients

The tax gene of human T-lymphotropic virus type 1 (HTLV-1) diverges among isolates according to geographic regions and has been classified into two genotypes: taxA and taxB. In Brazil, taxA is the most prevalent genotype in symptomatic and asymptomatic carriers. Few studies have been conducted in HIV-infected patients. The present study characterized the tax gene (1059 bp) in 13 Brazilian HIV-1/HTLV-1-coinfected patients from the south and southeast regions. The results confirmed the transcontinental HTLV-1 subgroup A of the Cosmopolitan subtype and showed high nucleotide similarity both among Brazilian sequences and in relation to the ATK prototype (99.5% and 99.2%, respectively). Six nucleotide substitutions were highly conserved among isolates, ranging from 76.9% to 100%: C7401T, T7914C, C7920T, C7982T, G8231A, and A8367C. The presence of the Brazilian molecular signature of genotype taxA was confirmed in all of the isolates, and they clustered into two Latin American clusters, which confirms the double introduction of HTLV-1 in Brazil.

Prevalência e vulnerabilidade à infecção pelo HIV de moradores de rua em São Paulo, SP

OBJETIVO: Analisar a prevalência e o perfil de vulnerabilidade ao HIV de moradores de rua. MÉTODOS: Estudo transversal com amostra não probabilística de 1.405 moradores de rua usuários de instituições de acolhimento de São Paulo, SP, de 2006 a 2007. Foi realizado teste anti-HIV e aplicado questionário estruturado. O perfil de vulnerabilidade foi analisado pela frequência do uso do preservativo, considerando mais vulneráveis os que referiram o uso nunca ou às vezes. Foram utilizadas regressões logística e multinomial para estimar as medidas de efeito e intervalos de 95% de confiança. RESULTADOS: Houve predominância do sexo masculino (85,6%), média de 40,9 anos, ter cursado o ensino fundamental (72,0%) e cor não branca (71,5%). A prática homo/bissexual foi referida por 15,7% e a parceria ocasional por 62,0%. O número médio de parcerias em um ano foi de 5,4 e mais da metade (55,7%) referiu uso de drogas na vida, dos quais 25,7% relataram uso frequente. No total, 39,6% mencionaram ter tido uma doença sexualmente transmissível e 38,3% relataram o uso do preservativo em todas as relações sexuais. A prevalência do HIV foi de 4,9% (17,4% dos quais apresentaram também sorologia positiva para sífilis). Pouco mais da metade (55,4%) tinha acesso a ações de prevenção. A maior prevalência do HIV esteve associada a ser mais jovem (OR 18 a 29 anos = 4,0 [IC95% 1,54;10,46]), história de doença sexualmente transmissível (OR = 3,3 [IC95% 1,87;5,73]); prática homossexual (OR = 3,0 [IC95% 1,28;6,92]) e à presença de sífilis (OR = 2,4 [IC95% 1,13;4,93]). O grupo de maior vulnerabilidade foi caracterizado por ser mulher, jovem, ter prática homossexual, número reduzido de parcerias, parceria fixa, uso de drogas e álcool e não ter acesso a ações de prevenção e apoio social. CONCLUSÕES: O impacto da epidemia entre moradores de rua é elevado, refletindo um ciclo que conjuga exclusão, vulnerabilidade social e acesso limitado à prevenção.

Oral lesions as predictors of highly active antiretroviral therapy failure in Brazilian HIV-infected children

OBJECTIVES: Evaluate the accuracy of HIV-related oral lesions to predict immune and virologic failure on HIV-infected children in use of highly active antiretroviral therapy (HAART). STUDY DESIGN: Data for this cross-sectional analysis come from a longitudinal study being conducted through the HIV-AIDS Outpatient Unit, ENT Division, Hospital das Clinicas, Sao Paulo University Medical School. The study began in January 1990 and is still ongoing. The cut-off point for analyses purposes was December 2004. Subjects were 471 HIV-infected consecutive children attending the outpatient unit during this period, who enrolled regardless of medical or immunological status. The children have undertaken oral cavity examination, serum CD4(+) T-lymphocyte count, and, 271 of them, viral load measurement. Sensitivity, specificity, positive predictive value, negative predictive value and relative risk were calculated. RESULTS: Oral lesions had moderate sensitivity, high specificity and positive predictive value to predict immune failure. It had low sensitivity and positive predictive value, and high specificity to predict virologic failure. DISCUSSION AND CONCLUSIONS: Oral manifestations of HIV can be important markers for immune suppression and for virologic failure, in Brazilian children undergoing HAART.

Characterization of Primary Isolates of HIV Type 1 CRF28_BF, CRF29_BF, and Unique BF Recombinants Circulating in Sao Paulo, Brazil

We report for the first time the genetic and biological characterization of 10 HIV-1 primary isolates representing CRF28_BF and CRF29_BF together with additional unique BF recombinant forms (URFs) obtained by PBMC cocultivation. Recombination is an important factor promoting the increase in the genetic diversity of HIV-1. Notably, more than 20% of HIV-1 sequences worldwide were recombinants. Several recombinant viruses were reported in Brazil, and six circulating recombinant forms (CRFs) have been identified (CRF28_BF, CRF29_BF, CRF31_BC, CRF39_BF, CRF40_BF, and CRF46_BF). CRF28_BF and CRF29_BF were found to infect almost 30% of the patients in Sao Paulo State. The near full-length genomes of these 10 primary isolates were amplified by nested PCR in three overlapping segments, purified, and sequenced. Three samples were related to CRF28_BF, three to CRF29_BF, and four were unique recombinant forms (URFs), as determined by their breakpoint profile determined with the jpHMM program. Additionally, the coreceptor usage of these isolates was investigated in vitro using GHOST assays, which revealed three dual-tropic (X4/R5) viruses, four lymphotropic (X4) viruses, and three macrophage-tropic (R5) viruses with different V3-loop motifs, which challenges the notion that GWGR-carrying viruses are macrophage-tropic only. In sum, we report a much-anticipated well-characterized panel of viruses representing CRF28_BF, CRF29_BF, and URFs from Sao Paulo State, Brazil.

HIV-1 induces NALP3-inflammasome expression and interleukin-1 beta secretion in dendritic cells from healthy individuals but not from HIV-positive patients

Objective: NALP3-inflammasome is an innate mechanism, alternative to type-1 interferon, which is able to recognize nucleic acids and viruses in the cytoplasm and to induce pro-inflammatory response. Here, we hypothesized the involvement of inflammasome in the early defense against HIV-1 and in the full maturation of dendritic cells: for this, we evaluated the response of dendritic cells pulsed with HIV-1 in terms of inflammasome activation in healthy donors. Moreover, inflammasome response to HIV was evaluated in HIV-infected individuals. Design and methods: Monocyte-derived dendritic cells isolated from 20 healthy individuals (HC-DC) and 20 HIV-1-infected patients (HIV-DC) were pulsed with alditrithiol-2-inactivated HIV-1. We then analyzed inflammasome genes expression and interleukin-1 beta (IL-1 beta) secretion. Results: In HC-DC, HIV-1 induced higher NLRP3/NALP3 mRNA expression compared with other inflammasome genes such as NALP1/NLRP1 or IPAF/NLRC4 (P < 0.001). This augmented expression was accompanied by CASP1-increased and IL1B-increased mRNA levels and by a significant increment of IL-1b secretion (P < 0.05). Otherwise, HIV-1 failed to activate inflammasome and cytokine production in HIV-DC. HIV-DC showed an increased NLRP3/NALP3 basal expression, suggesting a chronic inflammatory profile of patients' immune cells. Conclusion: HIV-1 was able to induce a NALP3-inflammasome response in healthy individuals, indicating that this inflammasome could play a role in the first steps of HIV-1 infection; the consequent inflammatory process may be important for directing host immune response against the virus and/or disease progression. HIV-DC seemed to be chronically activated, but unresponsive against pathogens. Our findings could be of interest considering the ongoing research about dendritic cell manipulation and therapeutic strategies for AIDS involving dendritic cell-based immune-vaccines. (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

LTR point mutations in the Tax-responsive elements of HTLV-1 isolates from HIV/HTLV-1-coinfected patients

Background: In Virology Journal 2011, 8: 535, Neto et al. described point mutations into Tax-responsive elements (TRE) of the LTR region of HTLV-1 isolates from asymptomatic carriers from Sao Paulo, Brazil, and hypothesized that the presence of the G232A mutation in the TRE-1 increase viral proliferation and consequently the proviral load (PvL), while the A184G mutation in the TRE-2 do not have such effect. Findings: We performed the real-time PCR assay (pol) and sequenced LTR region of HTLV-1 isolates from 24 HIV/HTLV-1-coinfected patients without HTLV-1-associated diseases from the same geographic area. These sequences were classified as belonging to the transcontinental subgroup A of the Cosmopolitan subtype a. The frequency of G232A mutation (16/24, 66.7%) was high as much as 61.8% reported by Neto's in HTLV-1 asymptomatic carriers with high PvL. High frequency (13/24, 54.2%) of double mutations G232A and A184G was also detected in HIV/HTLV-1-coinfected patients. We did not quantify PvL, but comparative analyses of the cycle threshold (Ct) median values of the group of isolates presenting the mutated-types sequences (Ct 33.5, n = 16) versus the group of isolates with the wild-type sequences (Ct 32, n = 8) showed no statistical difference (p = 0.4220). Conclusion: The frequencies of mutated-type sequences in the TRE-1 and TRE-2 motifs were high in HIV/HTLV-1-coinfected patients from Sao Paulo, Brazil. If these LTR point mutations have predictive value for the development of HTLV-1-associated diseases or they correspond to the subtype of virus that circulate in this geographic area has to be determined.

Assessment of tuberculosis treatment accessibility for patients co-infected or not with the human immunodeficiency virus

This study aimed to evaluate accessibility to treatment for people with TB co-infected or not with HIV. This cross-sectional study addressed issues regarding accessibility to treatment in a city in the interior of Sao Paulo state, Brazil. The instrument Primary Care Assessment Tool was utilized with 95 people. To evaluate access to treatment, Student's t test was used. The mean scores of variables were analyzed separately and compared between two groups (people with TB co-infected with HIV and people with TB not co-infected with HIV). Mean scores showed that HIV co-infected people presented greater difficulties in gaining access than those not co-infected. Professionals visited co-infected people more often when compared to those not co-infected; the co-infected people almost never accessed treatment for their disease in the Health Unit nearest their home. There is, therefore, the need for greater integration and communication between the programs for treatment of Tuberculosis and STD/AIDS.

Frequency of subtype B and F1 dual infection in HIV-1 positive, Brazilian men who have sex with men

Background: Because various HIV vaccination studies are in progress, it is important to understand how often inter- and intra-subtype co/superinfection occurs in different HIV-infected high-risk groups. This knowledge would aid in the development of future prevention programs. In this cross-sectional study, we report the frequency of subtype B and F1 co-infection in a clinical group of 41 recently HIV-1 infected men who have sex with men (MSM) in Sao Paulo, Brazil. Methodology: Proviral HIV-1 DNA was isolated from subject's peripheral blood polymorphonuclear leukocytes that were obtained at the time of enrollment. Each subject was known to be infected with a subtype B virus as determined in a previous study. A small fragment of the integrase gene (nucleotide 4255-4478 of HXB2) was amplified by nested polymerase chain reaction (PCR) using subclade F1 specific primers. The PCR results were further confirmed by phylogenetic analysis. Viral load (VL) data were extrapolated from the medical records of each patient. Results: For the 41 samples from MSM who were recently infected with subtype B virus, it was possible to detect subclade F1 proviral DNA in five patients, which represents a co-infection rate of 12.2%. In subjects with dual infection, the median VL was 5.3 x 10(4) copies/ML, whereas in MSM that were infected with only subtype B virus the median VL was 3.8 x 10(4) copies/ML (p > 0.8). Conclusions: This study indicated that subtype B and F1 co-infection occurs frequently within the HIV-positive MSM population as suggested by large number of BF1 recombinant viruses reported in Brazil. This finding will help us track the epidemic and provide support for the development of immunization strategies against the HIV.

Age-Related Expansion of Tim-3 Expressing T Cells in Vertically HIV-1 Infected Children

As perinatally HIV-1-infected children grow into adolescents and young adults, they are increasingly burdened with the long-term consequences of chronic HIV-1 infection, with long-term morbidity due to inadequate immunity. In progressive HIV-1 infection in horizontally infected adults, inflammation, T cell activation, and perturbed T cell differentiation lead to an "immune exhaustion'', with decline in T cell effector functions. T effector cells develop an increased expression of CD57 and loss of CD28, with an increase in co-inhibitory receptors such as PD-1 and Tim-3. Very little is known about HIV-1 induced T cell dysfunction in vertical infection. In two perinatally antiretroviral drug treated HIV-1-infected groups with median ages of 11.2 yr and 18.5 yr, matched for viral load, we found no difference in the proportion of senescent CD28(-)CD57(+)CD8(+) T cells between the groups. However, the frequency of Tim-3(+)CD8(+) and Tim-3(+)CD4(+) exhausted T cells, but not PD-1(+) T cells, was significantly increased in the adolescents with longer duration of infection compared to the children with shorter duration of HIV-1 infection. PD-1(+)CD8(+) T cells were directly associated with T cell immune activation in children. The frequency of Tim-3(+)CD8(+) T cells positively correlated with HIV-1 plasma viral load in the adolescents but not in the children. These data suggest that Tim-3 upregulation was driven by both HIV-1 viral replication and increased age, whereas PD-1 expression is associated with immune activation. These findings also suggest that the Tim-3 immune exhaustion phenotype rather than PD-1 or senescent cells plays an important role in age-related T cell dysfunction in perinatal HIV-1 infection. Targeting Tim-3 may serve as a novel therapeutic approach to improve immune control of virus replication and mitigate age related T cell exhaustion.

Broad and Cross-Clade CD4(+) T-Cell Responses Elicited by a DNA Vaccine Encoding Highly Conserved and Promiscuous HIV-1 M-Group Consensus Peptides

T-cell based vaccine approaches have emerged to counteract HIV-1/AIDS. Broad, polyfunctional and cytotoxic CD4(+) T-cell responses have been associated with control of HIV-1 replication, which supports the inclusion of CD4(+) T-cell epitopes in vaccines. A successful HIV-1 vaccine should also be designed to overcome viral genetic diversity and be able to confer immunity in a high proportion of immunized individuals from a diverse HLA-bearing population. In this study, we rationally designed a multiepitopic DNA vaccine in order to elicit broad and cross-clade CD4(+) T-cell responses against highly conserved and promiscuous peptides from the HIV-1 M-group consensus sequence. We identified 27 conserved, multiple HLA-DR-binding peptides in the HIV-1 M-group consensus sequences of Gag, Pol, Nef, Vif, Vpr, Rev and Vpu using the TEPITOPE algorithm. The peptides bound in vitro to an average of 12 out of the 17 tested HLA-DR molecules and also to several molecules such as HLA-DP, -DQ and murine IA(b) and IA(d). Sixteen out of the 27 peptides were recognized by PBMC from patients infected with different HIV-1 variants and 72% of such patients recognized at least 1 peptide. Immunization with a DNA vaccine (HIVBr27) encoding the identified peptides elicited IFN-gamma secretion against 11 out of the 27 peptides in BALB/c mice; CD4(+) and CD8(+) T-cell proliferation was observed against 8 and 6 peptides, respectively. HIVBr27 immunization elicited cross-clade T-cell responses against several HIV-1 peptide variants. Polyfunctional CD4(+) and CD8(+) T cells, able to simultaneously proliferate and produce IFN-gamma and TNF-alpha, were also observed. This vaccine concept may cope with HIV-1 genetic diversity as well as provide increased population coverage, which are desirable features for an efficacious strategy against HIV-1/AIDS.

Human immunodeficiency virus prevalence, incidence, and residual risk of transmission by transfusions at Retrovirus Epidemiology Donor Study-II blood centers in Brazil

BACKGROUND: In Brazil nationally representative donor data are limited on human immunodeficiency virus (HIV) prevalence, incidence, and residual transfusion risk. The objective of this study was to analyze HIV data obtained over 24 months by the Retrovirus Epidemiology Donor Study-II program in Brazil. STUDY DESIGN AND METHODS: Donations reactive to third-and fourth-generation immunoassays (IAs) were further confirmed by a less-sensitive (LS) IA algorithm and Western blot (WB). Incidence was calculated for first-time (FT) donors using the LS-EIA results and for repeat donors with a model developed to include all donors with a previous negative donation. Residual risk was projected by multiplying composite FT and repeat donor incidence rates by HIV marker-negative infectious window periods. RESULTS: HIV prevalence among FT donors was 92.2/ 105 donations. FT and repeat donor and composite incidences were 38.5 (95% confidence interval [CI], 25.651.4), 22.5 (95% CI, 17.6-28.0), and 27.5 (95% CI, 22.0-33.0) per 100,000 person-years, respectively. Male and community donors had higher prevalence and incidence rates than female and replacement donors. The estimated residual risk of HIV transfusion transmission was 11.3 per 106 donations (95% CI, 8.4-14.2), which could be reduced to 4.2 per 106 donations (95% CI, 3.2-5.2) by use of individual-donation nucleic acid testing (NAT). CONCLUSION: The incidence and residual transfusion risk of HIV infection are relatively high in Brazil. Implementation of NAT will not be sufficient to decrease transmission rates to levels seen in the United States or Europe; therefore, other measures focused on decreasing donations by at-risk individuals are also necessary.

Quality of life among Brazilian women living with HIV/AIDS

The purpose of the present study was to assess quality of life (QoL) in Brazilian women living with HIV/AIDS, according to the World Health Organization Quality of Life HIV-BREF (WHOQoL-HIV-BREF) domains. A quantitative-based, cross-sectional, analytical study was carried out in healthcare centers specialized in assisting people living with HIV/AIDS, located in a municipality of the state of Sao Paulo, Brazil. One hundred and six women of age 18 years or more, users of the public healthcare system, participated in the study. Socio-demographic and clinical variables were collected using a specific questionnaire. Quality of life related variables were collected by means of the WHOQoL-HIV-BREF instrument. As per the QoL domains, study results show that the Spirituality domain reached a standardized mean score of 65.7, followed by the Physical (64.7), Psychological (60.6), Social Relationships (59.5), Independence (58.6), and Environment (54.5) domains. Results of the multiple regression analysis indicate that the women's employment or retirement, income greater than the minimum wage, and higher educational level were associated with a higher standardized mean score of QoL. However, recent HIV/AIDS diagnosis and exposure to antiretroviral agents for a period shorter than two years were negatively associated with QoL. It is critical that public policies favor an all-embracing social inclusion of these women, thus promoting better social conditions. Counseling, clinical follow-up immediately after the infection diagnosis, and initiation of antiretroviral treatment are crucial moments in the lives of these individuals.

Modeling the emergence of HIV-1 drug resistance resulting from antiretroviral therapy: Insights from theoretical and numerical studies

The use of antiretroviral therapy has proven to be remarkably effective in controlling the progression of human immunodeficiency virus (HIV) infection and prolonging patient's survival. Therapy however may fail and therefore these benefits can be compromised by the emergence of HIV strains that are resistant to the therapy. In view of these facts, the question of finding the reason for which drug-resistant strains emerge during therapy has become a worldwide problem of great interest. This paper presents a deterministic HIV-1 model to examine the mechanisms underlying the emergence of drug-resistance during therapy. The aim of this study is to determine whether, and how fast, antiretroviral therapy may determine the emergence of drug resistance by calculating the basic reproductive numbers. The existence, feasibility and local stability of the equilibriums are also analyzed. By performing numerical simulations we show that Hopf bifurcation may occur. The model suggests that the individuals with drug-resistant infection may play an important role in the epidemic of HIV. (C) 2011 Elsevier Ireland Ltd. All rights reserved.