Accomplishments in HIV prevention science: implications for stemming the epidemic

The past two decades have witnessed substantial advances in the science of preventing HIV infection. Although important issues remain and there is a need for continuing research, arguably the biggest challenge in preventing HIV transmission is the full implementation of existing preventive interventions worldwide.     

Single motherhood and mental health: implications for primary prevention

In this issue (page 639) Dr. Ellen L. Lipman and colleagues show that single motherhood is associated with an increased risk of affective disorder and poverty and with increased rates of mental health services utilization. These findings have important implications for primary prevention interventions that focus on the social determinants of family health. Studies have shown that higher levels of psychological distress among single mothers are more closely related to their exposure to stressors than to their personal vulnerability to stress. Research has also shown that the stresses that affect single-parent families are greater in degree but not in kind than those that affect other families. Therefore, intervention programs that address the needs of all families are preferable to those that target specific types of families. Community-based primary prevention programs can promote the well-being of all families by improving the social and economic conditions in which they live.     

Norovirus-host interaction: implications for disease control and prevention

Noroviruses (NVs) are a major cause of acute gastroenteritis epidemics in both developing and developed countries and affect people of all ages. Three main human histo-blood group antigens (HBGAs) - the ABO, Lewis and secretor families - are involved in NV recognition and eight strain-specific receptor-binding patterns in two major binding groups have been described. The receptor-binding interface is located at the outermost surface of the P domain of the viral capsid. Each interface contains two major binding sites and each site interacts with a carbohydrate side-chain of the HBGAs via multiple hydrogen bonds. Soluble HBGAs in human milk are able to block binding of NV to HBGA receptors, suggesting a potential decoy receptor for the protection of infants from NV infection. Phylogenetic analysis has revealed limited genetic relatedness among NVs with similar receptor-binding patterns. This review summarises and discusses recent advances and highlights implications for future studies in the control and prevention of NV gastroenteritis.     

Association of Y chromosome haplogroup I with HIV progression, and HAART outcome

The host genetic basis of differential outcomes in HIV infection, progression, viral load set point and highly active retroviral therapy (HAART) responses was examined for the common Y haplogroups in European Americans and African Americans. Accelerated progression to acquired immune deficiency syndrome (AIDS) and related death in European Americans among Y chromosome haplogroup I (Y-I) subjects was discovered. Additionally, Y-I haplogroup subjects on HAART took a longer time to HIV-1 viral suppression and were more likely to fail HAART. Both the accelerated progression and longer time to viral suppression results observed in haplogroup Y-I were significant after false-discovery-rate corrections. A higher frequency of AIDS-defining illnesses was also observed in haplogroup Y-I. These effects were independent of the previously identified autosomal AIDS restriction genes. When the Y-I haplogroup subjects were further subdivided into six I subhaplogroups, no one subhaplogroup accounted for the effects on HIV progression, viral load or HAART response. Adjustment of the analyses for population stratification found significant and concordant haplogroup Y-I results. The Y chromosome haplogroup analyses of HIV infection and progression in African Americans were not significant. Our results suggest that one or more loci on the Y chromosome found on haplogroup Y-I have an effect on AIDS progression and treatment responses in European Americans. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Successful simplification of HAART in patients with acute primary HIV infection

Aggressive treatment has been advocated for the management of primary HIV infection (PHI), but the composition and the optimal duration of therapy are still to be determined. In addition, time to undetectable viral load (VL), rate and duration of VL suppression as well as subsequent therapeutic choices remain issues widely debated. We evaluated the rate and duration of VL suppression in 12 consecutive patients with PHI given triple-drug treatment with zidovudine, lamivudine and indinavir (highly active antiretroviral therapy, HAART) at onset of the acute illness and subsequently switched to a simplified 2-NRTI-based regimen once VL suppression was maintained for at least 6 months. Throughout the study, no patient discontinued treatment because of symptoms attributed to the study medications. In the study population, undetectable VL was achieved after a median of 84 days (range: 67-135) on HAART and was maintained for a median of 194 days (range: 179-205) before simplification. After switching to simplified maintenace, undetectable VL was maintained in all patients for at least 6 months. Only one patient experienced virological failure, plasma HIV-RNA remaining suppressed for a median foliow-up of 33 months (15-54) and T-CD4+ being steadily higher than 500/mL in the remaining patients. Our results suggest that simplification of HAART in patients promptly treated during PHI and maintaining undetectable VL for at least 6 months before simplification may be a valid option capable of controlling viral replication and maintaining an optimal immunological profile for a prolonged time.     

HIV pathogenesis: mechanisms of susceptibility and disease progression

The understanding of the factors associated with HIV-1 acquisition and disease progression has been significantly advanced in the past few years. These factors can be broadly defined as intrinsic or acquired and are operative at the levels of disease acquisition and progression or both. Much recent attention has focused on the identification of allelic variants at specific genetic loci that alter either susceptibility to infection or the natural history of disease progression. In addition, a more detailed understanding of the immunologic responses to HIV-1 and factors that perturb these responses has greatly enhanced our understanding of the immunologic control of HIV-1 and the roles of cofactors in HIV-1 acquisition and disease progression.     

Associations between use of crack cocaine and HIV-1 disease progression: research findings and implications for mother-to-infant transmission

Recent in vitro and in vivo research has suggested that cocaine has a direct effect on the pathogenesis of AIDS. These findings are confirmed by epidemiological studies linking the use of injected, inhaled, and smoked (crack) cocaine and indicators of HIV disease progression, even among adherent users of highly active antiretroviral therapy. Recent studies of vertical HIV transmission suggest that cocaine use may play a role in mother-to-child infection via alteration of maternal immune responses, enhanced viral replication in maternal immune cells, or alterations in the immune systems of neonates or infants. The purpose of this article is to review research conducted over the past several decades on associations between use of cocaine and HIV disease progression, especially among HIV+ women, and to explore its potential relevance for understanding mother-to-infant transmission of HIV.     

Ligand-dependent tau filament formation: implications for Alzheimer's disease progression.

The mechanism through which arachidonic acid induces the polymerization of tau protein into filaments under reducing conditions was characterized through a combination of fluorescence spectroscopy and electron microscopy. Results show that polymerization follows a ligand-mediated mechanism, where binding of arachidonic acid is an obligate step preceding tau-tau interaction. Homopolymerization begins with rapid (on the order of seconds) nucleation, followed by a slower elongation phase (on the order of hours). Although essentially all synthetic filaments have straight morphology at early time points, they interact with thioflavin-S and monoclonal antibody Alz50 much like authentic paired helical filaments, suggesting that the conformation of tau protein is similar in the two filament forms. Over a period of days, synthetic straight filaments gradually adopt paired helical morphology. These results define a novel pathway of tau filament formation under reducing conditions, where oxidation may contribute to final paired helical morphology, but is not a necessary prerequisite for efficient nucleation or elongation of tau filaments.     

Cytokine involvement in viral permissiveness and the progression of HIV disease

Many viruses have evolved novel means of exploiting host defense mechanisms for their own survival. This exploitation may be best exemplified by the interrelationships between certain viruses and the host cytokine networks. Many viruses, including the human immunodeficiency virus type-1 (HIV-1), rely on the liberation and cellular action of host immune cytokines to expand their host cell range, to regulate their cellular expression, and to maintain their dormant state until the proper extracellular conditions arise. As again exemplified by HIV-1, viruses may also take an active role regulating cytokine expression and cell surface cytokine receptors. Because the viral life cycle, and in particular the HIV-1 life cycle, is so intertwined with cytokine regulatory networks, these networks represent potential points for therapeutic intervention. As our understanding of cellular cytokine pathways involved in viral infection and replication continues to expand, so too will our ability to design rational anti-viral therapies to alter multiple steps along the viral life cycle.     

HIV prevention in high-risk women in South Africa: condom use and the need for change

Introduction

Young women are at disproportionate risk of HIV infection in South Africa. Understanding risk behaviors and factors associated with ability to negotiate safe sex and condom use is likely to be key in curbing the spread of HIV. Traditionally prevention efforts have focused on creating behavioral changes by increasing knowledge about HIV/AIDS.

Methods

This was a cross-sectional analysis from a prospective observational cohort study of 245 women at a high-risk of HIV infection in KwaZulu-Natal, South Africa.

Results

Participants demonstrated a high level of HIV/AIDS knowledge. Overall, 60.3% of participants reported condom use. Reported condom use at last sexual encounter varied slightly by partner type (57.0% with steady versus 64.4% with casual partners), and self-perceived ability to choose to use a condom was significantly lower with steady partners compared to casual partners (p<0.01). In multivariate analysis, women who had high school education were more likely to use condoms at their last sex encounter compared to those with only primary school education (RR of 1.36 (95% Confidence Interval (CI) 1.06–1.75) and 1.46 (95% CI 1.13–1.88) for grades 8–10 and 11–12, respectively). Those who used condoms as a contraceptive method were twice as likely to use condoms compared to women who did not report using them as a contraceptive method. Greater perceived ability to choose to use condoms was associated with higher self-reported condom use at last encounter, irrespective of partner type (RR = 2.65 (95% CI 2.15–32.5).

Discussion

Self-perceived ability to use condoms, level of formal education and condom use as a contraceptive were all significantly associated with self-reported condom use at last sexual encounter. These findings suggest that that gender inequality and access to formal education, as opposed to lack of HIV/AIDS knowledge, prevent safer sexual practices in South Africa.     

Anti-amyloidogenic effects of antioxidants: implications for the prevention and therapeutics of Alzheimer's disease

Alzheimer's disease (AD) is one of the most common dementing disorders and has profound medical and social consequences. The initiating molecular event is unknown, and its pathophysiology is highly complex. However, free radical injury appears to be a fundamental process contributing to the neuronal death seen in this disorder, and many studies using surrogate markers of oxidative damage have provided evidence supporting this hypothesis. Various compounds with antioxidant ability attenuated the oxidative stress induced by amyloid beta-protein (Abeta) in studies done in vitro and in vivo. Moreover, various antioxidants have been reported to inhibit the formation and extension of beta-amyloid fibrils (fAbeta), as well as to destabilize preformed fAbeta in vitro. In cell culture experiments, destabilized fAbeta were suggested to be less toxic than intact fAbeta. In transgenic mice model studies, some antioxidant compounds reduced plaque burden in vivo. In this article, we review the recent advances in the research on the antioxidants that inhibit the formation of fAbeta, as well as destabilize preformed fAbeta. Although the mechanisms by which these compounds inhibit fAbeta formation from Abeta, and destabilize preformed fAbeta are still unclear, they could be key molecules for the development of preventives and therapeutics for AD.     

Different immune correlates associated with tumor progression and regression: implications for prevention and treatment of cancer

Observations show that humans and animals respond immunologically to most cancers. Why does the immune system then fail to control cancer? We argue from the literature that there is a commonality in the regulation of responses against most murine tumors, and that a major mechanism of escape may be deviation of an effective Th1, cytotoxic T lymphocyte response to a less effective response with a Th2 component. We examined this hypothesis with two well-studied murine tumors. We found, following primary tumor implantation, that resistance correlates with Th1 responses and IgG2a antibody production and progression with mixed Th1/Th2 responses and production of IgG1 and IgG2a antibodies. Resistance is associated with a modulation of the anti-tumor response towards the Th1 pole in both systems. We conclude that the immune responses against these two tumors are in accord with our hypothesis, and argue that this is likely to be true of many human and murine tumors. The correlation of IgG isotype of anti-tumor antibody with the Th1/Th2 nature of the anti-tumor response readily allows one to longitudinally monitor the changing nature of the anti-tumor response. We suggest that such monitoring can guide immunotherapy to maximize the effectiveness of the host’s immune response against cancer.     

Variations in Helicobacter pylori cytotoxin-associated genes and their influence in progression to gastric cancer: implications for prevention

Helicobacter pylori (HP) is a bacterium that colonizes the human stomach and can establish a long-term infection of the gastric mucosa. Persistent Hp infection often induces gastritis and is associated with the development of peptic ulcer disease, atrophic gastritis, and gastric adenocarcinoma. Virulent HP isolates harbor the cag (cytotoxin-associated genes) pathogenicity island (cagPAI), a 40 kb stretch of DNA that encodes components of a type IV secretion system (T4SS). This T4SS forms a pilus for the injection of virulence factors into host target cells, such as the CagA oncoprotein. We analyzed the genetic variability in cagA and other selected genes of the HP cagPAI (cagC, cagE, cagL, cagT, cagV and cag Gamma) using DNA extracted from frozen gastric biopsies or from clinical isolates. Study subjects were 95 cagA+ patients that were histologically diagnosed with chronic gastritis or gastric cancer in Venezuela and Mexico, areas with high prevalence of Hp infection. Sequencing reactions were carried out by both Sanger and next-generation pyrosequencing (454 Roche) methods. We found a total of 381 variants with unambiguous calls observed in at least 10% of the originally tested samples and reference strains. We compared the frequencies of these genetic variants between gastric cancer and chronic gastritis cases. Twenty-six SNPs (11 non-synonymous and 14 synonymous) showed statistically significant differences (P<0.05), and two SNPs, in position 1039 and 1041 of cagE, showed a highly significant association with cancer (p-value = 2.07×10⁻⁶), and the variant codon was located in the VirB3 homology domain of Agrobacterium. The results of this study may provide preliminary information to target antibiotic treatment to high-risk individuals, if effects of these variants are confirmed in further investigations.     

Advantage of rare HLA supertype in HIV disease progression

The highly polymorphic human leukocyte antigen (HLA) class I molecules help to determine the specificity and repertoire of the immune response. The great diversity of these antigen-binding molecules confers differential advantages in responding to pathogens, but presents a major obstacle to distinguishing HLA allele-specific effects. HLA class I supertypes provide a functional classification for the many different HLA alleles that overlap in their peptide-binding specificities. We analyzed the association of these discrete HLA supertypes with HIV disease progression rates in a population of HIV-infected men. We found that HLA supertypes alone and in combination conferred a strong differential advantage in responding to HIV infection, independent of the contribution of single HLA alleles that associate with progression of the disease. The correlation of the frequency of the HLA supertypes with viral load suggests that HIV adapts to the most frequent alleles in the population, providing a selective advantage for those individuals who express rare alleles.     

Refined analysis of the critical age ranges of childhood overweight: implications for primary prevention

Prevention-interventions would certainly benefit from a precise knowledge of the age range when the most pronounced increases in prevalence of overweight and obesity occur in the general population. Data of 15,662 subjects aged 2-18 years were obtained from a national representative health survey (German Health Interview and Examination Survey for Children and Adolescents (KiGGS)) conducted in Germany. Weight, height, and BMI z-scores were calculated relative to the UK 1990 reference, and prevalence of overweight and obesity was defined according to the IOTF (International Obesity Task Force) age- and sex-specific cut-offs. Univariate ANOVAs for overweight, obesity, weight, height, and BMI z-scores as dependent variables were employed to assess significant differences for these measures across various age levels. Significant analysis was followed by post-hoc comparisons using Bonferroni adjustments. The main effect of age was estimated using a multinomial logistic regression model, and by defining the first derivative of a polynomial spline function. Different eclectic slopes over the entire age range from 2 to 18 years have been observed. Prevalence of overweight substantially increases between the 5th and the 8th year (12.5-21.4%; P ≤ 0.001). Maximum increase of the polynomial fit was detected at 7.2 years. Our findings suggest a relatively narrow age range at the first school year when overweight in German children especially increases. We therefore propose that psychosocial correlates may be related to the general life-time event around the age of entering school.     

Resource implications and health benefits of primary prevention strategies for cardiovascular disease in people aged 30 to 74: mathematical modelling study

ObjectiveTo develop a model to determine resource costs and health benefits of implementing guidelines for the prevention of cardiovascular disease in primary care.DesignModelling of data from six strategies for prevention of cardiovascular disease. Strategies incorporated two ways of identifying patients for assessment: traditional (assessment of all adults) and novel (preselection of patients for assessment using a prior estimate of their risk of cardiovascular disease). Three treatment strategies were modelled in conjunction with each identification strategy.SettingEngland.SubjectsPatients aged 30 to 74 eligible for primary prevention strategies for cardiovascular disease who were selected from a hypothetical population of 2000.ResultsNovel strategies prevented more cardiovascular disease, at lower cost, than traditional strategies. Some treatment strategies prevent more cardiovascular disease with fewer resources than others. The findings were robust across a range of different assumptions about workload.ConclusionPreselecting patients for assessment makes better use of staff time than assessing all adults. Treating many patients with low cost drugs is more efficient than prescribing a few patients intensive antihypertensives and statins. Authors of guidelines should model workload implications and health benefits of following their recommendations.

What is already known on this topic

It is possible to estimate patients'' risk of cardiovascular disease and their probability of benefiting from treatmentThere are data on the distribution of cardiovascular risk factors in the population

What this study adds

A model estimated the efficiency of six strategies for primary prevention of cardiovascular disease: three strategies followed guidelines and three prioritised patients for assessment on the basis of a prior estimate of cardiovascular riskStrategies that prioritise patients for risk assessment may reduce staff time to the extent that more patients can be treated and more disease prevented within available resourcesStatins and angiotensin converting enzyme inhibitors cost more than identifying and treating new patients, so strategies avoiding these may allow more disease to be prevented within available resources     

Overestimates of survival after HAART: implications for global scale-up efforts

Background

Monitoring the effectiveness of global antiretroviral therapy scale-up efforts in resource-limited settings is a global health priority, but is complicated by high rates of losses to follow-up after treatment initiation. Determining definitive outcomes of these lost patients, and the effects of losses to follow-up on estimates of survival and risk factors for death after HAART, are key to monitoring the effectiveness of global HAART scale-up efforts.

Methodology/Principal Findings

A cohort study comparing clinical outcomes and risk factors for death after HAART initiation as reported before and after tracing of patients lost to follow-up was conducted in Botswana''s National Antiretroviral Therapy Program. 410 HIV-infected adults consecutively presenting for HAART were evaluated. The main outcome measures were death or loss to follow-up within the first year after HAART initiation. Of 68 patients initially categorized as lost, over half (58.8%) were confirmed dead after tracing. Patient tracing resulted in reporting of significantly lower survival rates when death was used as the outcome and losses to follow-up were censored [1-year Kaplan Meier survival estimate 0.92 (95% confidence interval, 0.88–0.94 before tracing and 0.83 (95% confidence interval, 0.79–0.86) after tracing, log rank P<0.001]. In addition, a significantly increased risk of death after HAART among men [adjusted hazard ratio 1.74 (95% confidence interval, 1.05–2.87)] would have been missed had patients not been traced [adjusted hazard ratio 1.41 (95% confidence interval, 0.65–3.05)].

Conclusions/Significance

Due to high rates of death among patients lost to follow-up after HAART, survival rates may be inaccurate and important risk factors for death may be missed if patients are not actively traced. Patient tracing and uniform reporting of outcomes after HAART are needed to enable accurate monitoring of global HAART scale-up efforts.