Selection of T-cell vaccine antigens for chronic persistent viral infections has been largely empirical. To define the relationship, at the population level, between the specificity of the cellular immune response and viral control for a relevant human pathogen, we performed a comprehensive analysis of the 160 dominant CD8(+) T-cell responses in 578 untreated HIV-infected individuals from KwaZulu-Natal, South Africa. Of the HIV proteins targeted, only Gag-specific responses were associated with lowering viremia. Env-specific and Accessory/Regulatory protein-specific responses were associated with higher viremia. Increasing breadth of Gag-specific responses was associated with decreasing viremia and increasing Env breadth with increasing viremia. Association of the specific CD8(+) T-cell response with low viremia was independent of HLA type and unrelated to epitope sequence conservation. These population-based data, suggesting the existence of both effective immune responses and responses lacking demonstrable biological impact in chronic HIV infection, are of relevance to HIV vaccine design and evaluation.

No abstract

The extreme polymorphism in the human leukocyte antigen (HLA) class I region of the human genome is suggested to provide an advantage in pathogen defence mediated by CD8+ T cells. HLA class I molecules present pathogen-derived peptides on the surface of infected cells for recognition by CD8+ T cells. However, the relative contributions of HLA-A and -B alleles have not been evaluated. We performed a comprehensive analysis of the class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1), immune control of which is dependent upon virus-specific CD8+ T-cell activity. In 375 HIV-1-infected study subjects from southern Africa, a significantly greater number of CD8+ T-cell responses are HLA-B-restricted, compared to HLA-A (2.5-fold; P = 0.0033). Here we show that variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, is strongly associated with particular HLA-B but not HLA-A allele expression (P < 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). These data indicate that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles. The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design.

Since the 2009 Lancet Health in South Africa Series, important changes have occurred in the country, resulting in an increase in life expectancy to 60 years. Historical injustices together with the disastrous health policies of the previous administration are being transformed. The change in leadership of the Ministry of Health has been key, but new momentum is inhibited by stasis within the health management bureaucracy. Specific policy and programme changes are evident for all four of the so-called colliding epidemics: HIV and tuberculosis; chronic illness and mental health; injury and violence; and maternal, neonatal, and child health. South Africa now has the world's largest programme of antiretroviral therapy, and some advances have been made in implementation of new tuberculosis diagnostics and treatment scale-up and integration. HIV prevention has received increased attention. Child mortality has benefited from progress in addressing HIV. However, more attention to postnatal feeding support is needed. Many risk factors for non-communicable diseases have increased substantially during the past two decades, but an ambitious government policy to address lifestyle risks such as consumption of salt and alcohol provide real potential for change. Although mortality due to injuries seems to be decreasing, high levels of interpersonal violence and accidents persist. An integrated strategic framework for prevention of injury and violence is in progress but its successful implementation will need high-level commitment, support for evidence-led prevention interventions, investment in surveillance systems and research, and improved human-resources and management capacities. A radical system of national health insurance and re-engineering of primary health care will be phased in for 14 years to enable universal, equitable, and affordable health-care coverage. Finally, national consensus has been reached about seven priorities for health research with a commitment to increase the health research budget to 2·0% of national health spending. However, large racial differentials exist in social determinants of health, especially housing and sanitation for the poor and inequity between the sexes, although progress has been made in access to basic education, electricity, piped water, and social protection. Integration of the private and public sectors and of services for HIV, tuberculosis, and non-communicable diseases needs to improve, as do surveillance and information systems. Additionally, successful interventions need to be delivered widely. Transformation of the health system into a national institution that is based on equity and merit and is built on an effective human-resources system could still place South Africa on track to achieve Millennium Development Goals 4, 5, and 6 and would enhance the lives of its citizens.

In the first article in a series on maternal, newborn, and child health in sub-Saharan Africa, Joy Lawn and colleagues outline where and why deaths among mothers and children occur and what known interventions can be employed to prevent these deaths.

Stunting is common in young children in developing countries, and is associated with increased morbidity, developmental delays, and mortality. Its complex pathogenesis likely involves poor intrauterine and postnatal nutrition, exposure to microbes, and the metabolic consequences of repeated infections. Acquired enteropathy affecting both gut structure and function likely plays a significant role in this outcome, especially in the first few months of life, and serve as a precursor to later interactions of infection and malnutrition. However, the lack of validated clinical diagnostic criteria has limited the ability to study its role, identify causative factors, and determine cost-effective interventions. This review addresses these issues through a historical approach, and provides recommendations to define and validate a working clinical diagnosis and to guide critical research in this area to effectively proceed. Prevention of early gut functional changes and inflammation may preclude or mitigate the later adverse vicious cycle of malnutrition and infection.

No abstract

Background: Few studies address the use of paediatric highly active antiretroviral therapy (HAART) in Africa.