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IntroductionLong-term natural history cohorts of HIV-1 in the absence of treatment provide the best measure of virulence by different viral subtypes.MethodsNewly HIV infected Ugandan and Zimbabwean women (N = 303) were recruited and monitored for clinical, social, behavioral, immunological and viral parameters for 3 to 9.5 years.ResultsUgandan and Zimbabwean women infected with HIV-1 subtype C had 2.5-fold slower rates of CD4 T-cell declines and higher frequencies of long-term non-progression than those infected with subtype A or D (GEE model, P < 0.001), a difference not associated with any other clinical parameters. Relative replicative fitness and entry efficiency of HIV-1 variants directly correlated with virulence in the patients, subtype D > A > C (P < 0.001, ANOVA).DiscussionHIV-1 subtype C was less virulent than either A or D in humans; the latter being the most virulent. Longer periods of asymptomatic HIV-1 subtype C could explain the continued expansion and dominance of subtype C in the global epidemic.

Human immunodeficiency virus type 1 (HIV-1) subtype C is the dominant subtype globally, due largely to the incidence of subtype C infections in sub-Saharan Africa and east Asia. We compared the relative replicative fitness (ex vivo) of the major (M) group of HIV-1 subtypes A, B, C, D, and CRF01_AE and group O isolates. To estimate pathogenic fitness, pairwise competitions were performed between CCR5-tropic (R5) or CXCR4-tropic (X4) virus isolates in peripheral blood mononuclear cells (PBMC). A general fitness order was observed among 33 HIV-1 isolates; subtype B and D HIV-1 isolates were slightly more fit than the subtype A and dramatically more fit than the 12 subtype C isolates. All group M isolates were more fit (ex vivo) than the group O isolates. To estimate ex vivo transmission fitness, a subset of primary HIV-1 isolates were examined in primary human explants from penile, cervical, and rectal tissues. Only R5 isolates and no X4 HIV-1 isolates could replicate in these tissues, whereas the spread to PM1 cells was dependent on active replication and passive virus transfer. In tissue competition experiments, subtype C isolates could compete with and, in some cases, even win over subtype A and D isolates. However, when the migratory cells from infected tissues were mixed with a susceptible cell line, the subtype C isolates were outcompeted by other subtypes, as observed in experiments with PBMC. These findings suggest that subtype C HIV-1 isolates might have equal transmission fitness but reduced pathogenic fitness relative to other group M HIV-1 isolates.

These subtype differences in coreceptor use may partially explain the faster progression rates we have previously reported in individuals infected with subtype D compared with subtype A. Our observations may have implications for the future use of coreceptor inhibitors in this population.

Replication studies on human immunodeficiency virus 1 (HIV-1) rely on a few laboratory strains that are divergent from dominant HIV-1 subtypes in the epidemic. Several phenotypic differences between diverse HIV-1 isolates and subtypes could affect vaccine development and treatment, but this research field lacks robust cloning/virus production systems to study drug sensitivity, replication kinetics, or to develop personalized vaccines. Extreme HIV-1 heterogeneity leaves few restriction enzyme sites for bacterial cloning strategies. In this study, we describe an alternative approach that involves direct introduction of any HIV-1 coding regions (e.g., any gene from a patient sample) into an HIV-1 DNA vector using yeast recombination. This technique uses positive and negative selectable markers in yeast and avoids the need for purification and screening of the DNA substrates and cloning products. Replication-competent virus is then produced from a modified mammalian 293T packaging cell line transfected with this yeast-derived HIV-1 vector. Although HIV-1 served as the prototype, this cloning strategy is now being developed for other diverse virus species such as hepatitis C virus and influenza virus.

Patterns of drug resistance after virological failure on first-line ART are similar in adults and children in sub-Saharan Africa. Improved VL monitoring to prevent accumulation of mutations, and new drug classes to construct fully active regimens, are required.

Exclusive breastfeeding (EBF) is being promoted by WHO/UNICEF as the recommended mode of feeding for all infants from birth to around 6 months of age. It is also recommended for the initial few months, for infants born to HIV-positive mothers in the developing world where conditions may not be ideal for replacement feeding. A cross-sectional study was done to find the prevalence and factors associated with EBF from delivery, amongst mothers of infants 0-6 months of age in a rural Ugandan community with a high HIV/AIDS burden. A prevalence of EBF of 35.1 per cent was found. There was a very high use of prelacteal feeds. Factors positively associated with EBF from birth, after logistic regression, were: delivery from a health unit (OR 2.07; 95 per cent confidence interval, 1.2-3.6); and mother having a normal vaginal delivery (OR 10.54; 95 per cent CI, 3.0-36.6). Factors showing negative association were: male gender of child (OR 0.44; 95 per cent CI, 0.3-0.7); and age of child over 3 months (OR 0.48; 95 per cent CI, 0.3-0.7). Mothers knowledge of her HIV serostatus was not associated with EBF (p = 0.78). Breastfeeding is almost universal in this area but it is rarely exclusive from birth.

Objectives To determine the impact of HIV-1 subtype on treatment outcomes and the emergence of drug resistance in the resource limited setting of Kampala, Uganda. Design The Joint Clinical Research Centre (JCRC) in Kampala, Uganda has provided over 2000 drug-resistant genotypes (DRGs) over the past 10 years as standard of care for patients failing therapy and 1403 from treatment-naive and experienced patients over the past 10 years have been analyzed for this study. Method Viral loads, CD4 cell count, treatment histories and other relevant clinical data was compared with the infecting HIV-1 subtype and DRGs of Ugandan patients failing treatment. Results Patients failing HAART with DRGs (n = 937) were more frequently infected with subtype D than expected on the basis of the subtype distribution in the treatment-naive population (n = 655) in Kampala (P < 0.001). Higher proportions of treatment failures among subtype D-infected patients were driven by resistance to nucleoside reverse transcriptase inhibitors (NRTI) (P < 0.0002) more than to non-NRTIs (P > 0.04) or protease inhibitors. Conclusion Higher rates of treatment failure among subtype D as compared with subtype A-infected Ugandans was analogous to the faster disease progression in subtype D-infected patients. The mechanism(s) by which drug resistance may emerge faster in subtype D HIV-1 may relate to higher replicative fitness and increased propensity for a CXCR4 tropism.