Host genetic determinants of T cell responses to the MRKAd5 HIV-1 gag/pol/nef vaccine in the step trial

Understanding how human genetic variation impacts individual response to immunogens is fundamental for rational vaccine development. To explore host mechanisms involved in cellular immune responses to the MRKAd5 human immunodeficiency virus type 1 (HIV-1) gag/pol/nef vaccine tested in the Step trial, we performed a genome-wide association study of determinants of HIV-specific T cell responses, measured by interferon γ enzyme-linked immunospot assays. No human genetic variant reached genome-wide significance, but polymorphisms located in the major histocompatibility complex (MHC) region showed the strongest association with response to the HIV-1 Gag protein: HLA-B alleles known to be associated with differences in HIV-1 control were responsible for these associations. The implication of the same HLA alleles in vaccine-induced cellular immunity and in natural immune control is of relevance for vaccine design. Furthermore, our results demonstrate the importance of considering the host immunogenetic background in the analysis of immune responses to T cell vaccines.     

Codon usage optimization of HIV type 1 subtype C gag, pol, env, and nef genes: in vitro expression and immune responses in DNA-vaccinated mice

Codon usage optimization of human immunodeficiency virus type 1 (HIV-1) structural genes has been shown to increase protein expression in vitro as well as in the context of DNA vaccines in vivo; however, all optimized genes reported thus far are derived from HIV-1 (group M) subtype B viruses. Here, we report the generation and biological characterization of codon usage-optimized gag, pol, env (gp160, gp140, gp120), and nef genes from a primary (nonrecombinant) HIV-1 subtype C isolate. After transfection into 293T cells, optimized subtype C genes expressed one to two orders of magnitude more protein (as determined by immunoblot densitometry) than the corresponding wild-type constructs. This effect was most pronounced for gp160, gp140, Gag, and Pol (>250-fold), but was also observed for gp120 and Nef (45- and 20-fold, respectively). Optimized gp160- and gp140-derived glycoproteins were processed, incorporated into virus particles, and mediated virus entry when expressed in trans to complement an env-minus HIV-1 provirus. Mice immunized with optimized gp140 DNA developed antibody as well as CD4+ and CD8+ T cell immune responses that were orders of magnitude greater than those of mice immunized with wild-type gp140 DNA. These data confirm and extend previous studies of codon usage optimization of HIV-1 genes to the most prevalent group M subtype. Our panel of matched optimized and wild-type subtype C genes should prove valuable for studies of protein expression and function, the generation of subtype-specific immunological reagents, and the production of DNA-based sub-unit vaccines directed against a broader spectrum of viruses.     

Characterization of the South African HIV type 1 subtype C complete 5' long terminal repeat, nef, and regulatory genes

Human immunodeficiency virus type 1 (HIV-1) subtype C has become the major etiological agent in the global and especially African epidemic. To gain better understanding of the genetic diversity and rapid transmission of HIV-1 subtype C, we have characterized the complete 5' long terminal repeat (LTR) region along with the regulatory genes tat and rev as well as the accessory gene nef of 14 South African HIV-1 subtype C isolates. Phylogenetic analysis revealed a subtype C 5' LTR cluster, as well as subclustering of our nef sequences with various subtype C strains separate from the India and China subclusters. At least 3 NF-kappaB sites were present in the 5' LTR of most isolates and 13 isolates had the subtype C-specific Rev truncation. Some length variation in exon 2 and the absence of a critical cysteine were found in Tat. Residue variation in the myristoylation signal and motifs involved in CD4 and MHC-I downregulation was recorded in our nef gene sequences.     

Meningitis due to beta-lactamase producing, chloramphenicol-resistant Haemophilus influenzae type b, in South Africa

A case of meningitis and septicaemia due to Haemophilus influenzae type b resistant to both ampicillin and chloramphenicol is reported. After initial failure of chloramphenicol therapy, the patient responded to cefotaxime alone. To our knowledge, this represents the first such reported case in South Africa.     

Sequence analysis of env C2/V3, gag p17/p24, and pol protease regions of 25 HIV type 1 isolates from Ho Chi Minh City, Vietnam

Env C2/V3, gag p17/p24, pol protease, and RT regions of HIV-1 isolates recently obtained from 25 HIV-1 seropositive individuals from Ho Chi Minh City (Vietnam) were studied, and genes subtypes were determined by DNA sequence analyses. Twenty-three isolates out of 25 were identified as belonging to subtype E, now recognized as circulating recombinant form 1 (CRF01_AE). The motif at the top of the V3 loop (generally GPGQ) was then preceded by an isoleucine or a methionine (M) residue; the M residue might be a local signature of Vietnamese E isolates compared to Thai E viruses. Two isolates (8%) were shown to be intersubtype recombinants: one E/B and one CRF02_AG(IBNG)/D. The polymorphism of pol protease was considered only for CRF01_AE isolates and is clearly different from that recorded for B viruses with substitutions at positions 13, 35, 36, 41, 69, and 89.     

High frequency of gross deletions in the 5' LTR and gag regions in HIV type 1-infected long-term survivors treated with Korean red ginseng

Our previous studies have shown that gross deletions in the nef gene as well as slow decreases in CD4 T cell numbers are associated with Korean red ginseng (KRG) intake in HIV-1-infected patients. To determine whether there might be an association between KRG intake and occurrence of gross deletions (gDelta) in the 5' LTR and gag regions, we examined the 1125 base pair (bp) sequences encompassing these regions in 10 long-term survivors (LTSs) treated with KRG (total of 13,364 +/- 5364 g) for > 12 years, and in 8 LTS control patients with no or minimal (total of 1436 +/- 1027 g) KRG intake (LTS controls). In the 10 LTSs, 189 PCR products were obtained from 80 peripheral blood mononuclear cell (PBMC) samples. In total, 44 of the 80 PBMC samples (55%) and 71 of the 189 PCR products (37.6%) displayed gDelta. While 55% of PBMC samples and 37.6% of PCR products showed gDelta in the 10 LTSs, the corresponding figures for the eight LTS controls were 30.3% and 14.8%. These differences were significant (p < 0.05 and p = 0, respectively). In addition, the proportions of 28 patients in the general population (without KRG intake) displaying PBMC and PCR gDelta were 13.3% and 8.3%, respectively. Our data strongly suggest that gDelta occurrence in the HIV-1 5' LTR and gag regions is associated with KRG intake.     

HIV/AIDS/STI/TB knowledge, beliefs and practices of traditional healers in KwaZulu-Natal, South Africa

The aim of this study was investigate the HIV/AIDS/STI and TB knowledge, beliefs and practices of traditional healers in South Africa. In a cross-sectional study 233 traditional healers were interviewed in three selected communities in KwaZulu-Natal. Results indicate that the most common conditions seen were STIs, a variety of chronic conditions, HIV/AIDS (20%) and tuberculosis (29%). Although most healers had a correct knowledge of the major HIV transmission routes, prevention methods and ARV treatment, their knowledge was poorer on other HIV transmission routes, and 21% believed that there is a cure for AIDS. A minority reported unsafe practices in terms of reuse of razor blades on more than one patients and the reuse of enema equipment without sterilization, and two-thirds used gloves when carrying out scarifications. Randomized control trials are called for to test the effectiveness of traditional healing for HIV/AIDS, STI and TB prevention and care.     

Durable responses after ibritumomab tiuxetan radioimmunotherapy for CD20+ B-cell lymphoma: long-term follow-up of a phase 1/2 study

We previously demonstrated that yttrium-90 (Y-90) ibritumomab tiuxetan (Zevalin) radioimmunotherapy (RIT) was safe and effective for relapsed or refractory CD20(+), B-cell, non-Hodgkin lymphoma (NHL). We now provide long-term follow-up data in responding patients based on International Workshop Response Criteria. Complete (CR), CR unconfirmed (CRu), and partial response (PR) rates were 29%, 22%, and 22%, respectively (overall response rate 73%, 51% in CR/CRu). Mean time to progression (TTP) and duration of response (DR) in responders were 12.6 months and 11.7 months, respectively. At the maximum tolerated dose (0.4 mCi/kg [14.8 MBq/kg]), TTP and DR in complete responders (CR/CRu) were 28.3 and 27.5 months, respectively. Nine patients (24% of responding patients) had a TTP of more than 3 years. Long-term responders (> 5 years) have been identified. Ibritumomab tiuxetan produces durable responses in patients with indolent and diffuse large B-cell lymphoma.     

Clinical and social determinants of diarrhoeal disease in a rural HIV/AIDS clinic, South Africa: a case-control study

Diarrhoeal diseases are a common cause of morbidity and are associated with mortality in HIV-infected populations. Little is known about the contribution of clinical and socio-environmental factors to the risk of diarrhoea in these populations in rural sub-Saharan Africa. We conducted a case-control study of people attending a rural HIV clinic with an episode of diarrhoea in Bushbuckridge, South Africa. Cases were defined as HIV-positive adults with symptoms of diarrhoea before or after initiation of antiretroviral therapy (ART). Controls without diarrhoea were randomly selected from clinic attendees. Structured questionnaires and case-file reviews were undertaken to describe clinical and socioenvironmental risk factors. We recruited 103 cases of diarrhoea from 121 patients meeting case definitions. Cases were more likely to be women (P = 0.013), aged over 45 years (P = 0.002), divorced or separated (P = 0.006), have limited formal education (P = 0.003), have inadequate access to sanitation facilities (P = 0.045), have water access limited to less than three days per week (P = 0.032) and not yet initiated on ART (P < 0.001). In multivariate analysis, diarrhoea remained associated with female gender (adjusted odds ratio [aOR]: 2.02, 95% CI 1.10-3.73), older age (aOR: 6.31, 95% CI 1.50-26.50), limited access to water (aOR: 2.66, 95% CI 1.32-5.35) and pre-ART status (aOR: 5.87, 95% CI 3.05-11.27). Clinical and socio-environmental factors are associated with occurrence of diarrhoeal disease among rural HIV patients in South Africa. Further intervention research is urgently needed, combining community- and clinic-based approaches, to improve access to water, sanitation and ART for rural areas with high HIV prevalence, along with structural interventions to address gender inequities.     

Mortality and causes of death in type 2 diabetic patients. A long-term follow-up study in Osaka District, Japan

A follow-up study of 1939 diabetic patients with a mean observation period of 9.4 years was carried out in Osaka, Japan. The mortality rates per 1000 person-years were 31.35 for males and 21.99 for females, and the ratios of observed to expected number of deaths were 1.69 for males and 1.74 for females, indicating an excess mortality for diabetic patients of both sexes and higher mortality in males than in females in Japan. Factors related to the prognosis of the patients were age, elevated fasting glucose level, lower obesity index, hypertension, diabetic retinopathy, and albuminuria at entry to the study. Insulin treatment was also associated with poor prognosis. Cerebro-cardiovascular and renal disease were the major causes of death in diabetic patients; heart disease killed 19.5%, cerebrovascular disease 16.7% and renal disease 13.1%. The relatively high frequency of renal disease as a cause of death in type 2 diabetes, especially in patients with a lower age of onset, was noteworthy, suggesting some difference in the clinical manifestations of diabetes between Japan and Western countries. Malignant neoplasms accounted for 25% of deaths, and cirrhosis of the liver for 6.4%.     

The impact of the HIV epidemic on the composite wellbeing of educators in South Africa: a qualitative study

In South Africa, support is available for educators who are HIV-positive, and there are numerous initiatives to curb further HIV infections. What is lacking though is an understanding of how the HIV epidemic impacts on educators who are affected personally or professionally. For this reason a qualitative study was undertaken with 25 affected educators from the Gauteng and Free State provinces. Semi-structured interviews were conducted to determine how the epidemic is impacting the health of educators who are affected but not HIV infected. The results suggest that affected educators are in need of interventions that target health promotion, since those who participated reported poor physical, emotional, social, spiritual and professional health. The results also suggest that some educators do cope with the overall impact of the epidemic, implying that resilient functioning among affected educators should be promoted.     

Understanding of the risk of HIV infection among the elderly in Ga-Rankuwa,South Africa

Abstract

The literature pertaining to the elderly shows that HIV infection among this population is on the increase, suggesting that the elderly population engages in activities risky for HIV infection. Reports on such behaviour include frequent sexual relations with much younger people and having multiple partners. A study was carried out in Ga-Rankuwa, a black township in Gauteng Province, South Africa to explore and describe the understanding of these elderly people regarding their risks of HIV infection and AIDS. Using a qualitative, exploratory design, three focus-group interviews were conducted with 32 women aged over 50 years. Findings revealed that older persons have knowledge about transmission of HIV infection and AIDS. However, a few had misconceptions as to how HIV infection is transmitted, as they believed that poor nutrition and sharing facilities play a role. Knowledge of mechanisms of protecting themselves against infection, such as use of a condom during coitus and wearing gloves when caring for infected family members, was also evident. The elderly indicated that they would prefer an older person, who they could identify with, to educate them more about HIV infection and AIDS. Although majority of participants had knowledge of how HIV is transmitted, and issues that put them at risk of transmission, a few the older persons had misconceptions about how HIV is transmitted due to lack of knowledge, as they believed that poor nutrition and sharing facilities can transmit infection. The lack of knowledge underscores the importance of addressing sexual risk with older people. It was very clear that more needs to be done in terms of education campaigns to dispel the myths of HIV infection and to empower the elderly.     

‘The mercurial piece of the puzzle’: Understanding stigma and HIV/AIDS in South Africa

Although stigma and its relationship to health and disease is not a new phenomenon, it has not been a major feature in the public discourse until the emergence of HIV. The range of negative responses associated with the epidemic placed stigma on the public agenda and drew attention to its complexity as a phenomenon and concept worthy of further investigation. Despite the consensus that stigma is one of the major contributors to the rapid spread of HIV and the frequent use of the term in the media and among people in the street, the exact meaning of ‘stigma’ remains ambiguous. The aim of this paper is to briefly re-visit some of the scholarly deliberations and further interrogate their relevance in explaining HIV-related stigma evidenced in South Africa. In conclusion a model is presented. Its usefulness – or explanatory potential – is that it attempts to provide a comprehensive framework that offers insights into the individual as well as the social/structural components of HIV-related stigma in a particular context. As such, it has the potential to provide more nuanced understandings as well as to alert us to knowledge-gaps in the process.