Building knowledge, optimising physical and mental health and setting up healthier life trajectories in South African women (Bukhali): a preconception randomised control trial part of the Healthy Life Trajectories Initiative (HeLTI).

INTRODUCTION: South Africa's evolving burden of disease is challenging due to a persistent infectious disease, burgeoning obesity, most notably among women and rising rates of non-communicable diseases (NCDs). With two thirds of women presenting at their first antenatal visit either overweight or obese in urban South Africa (SA), the preconception period is an opportunity to optimise health and offset transgenerational risk of both obesity and NCDs. METHODS AND ANALYSIS: Bukhali is the first individual randomised controlled trial in Africa to test the efficacy of a complex continuum of care intervention and forms part of the Healthy Life Trajectories Initiative (HeLTI) consortium implementing harmonised trials in Canada, China, India and SA. Starting preconception and continuing through pregnancy, infancy and childhood, the intervention is designed to improve nutrition, physical and mental health and health behaviours of South African women to offset obesity-risk (adiposity) in their offspring. Women aged 18-28 years (n=6800) will be recruited from Soweto, an urban-poor area of Johannesburg. The primary outcome is dual-energy X-ray absorptiometry derived fat mass index (fat mass divided by height2) in the offspring at age 5 years. Community health workers will deliver the intervention randomly to half the cohort by providing health literacy material, dispensing a multimicronutrient supplement, providing health services and feedback, and facilitating behaviour change support sessions to optimise: (1) nutrition, (2) physical and mental health and (3) lay the foundations for healthier pregnancies and early child development. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Human Ethics Research Committee University of the Witwatersrand, Johannesburg, South Africa (M1811111), the University of Toronto, Canada (19-0066-E) and the WHO Ethics Committee (ERC.0003328). Data and biological sample sharing policies are consistent with the governance policy of the HeLTI Consortium (https://helti.org) and South African government legislation (POPIA). The recruitment and research team will obtain informed consent. TRIAL REGISTRATION: This trial is registered with the Pan African Clinical Trials Registry (https://pactr.samrc.ac.za) on 25 March 2019 (identifier: PACTR201903750173871). PROTOCOL VERSION: 20 March 2022 (version #4). Any protocol amendments will be communicated to investigators, Institutional Review Board (IRB)s, trial participants and trial registries.

COVID-19 antibody testing: From hype to immunological reality.

The potential role for serological tests in the current COVID-19 pandemic has generated very considerable recent interest across many sectors worldwide, inter alia pathologists seeking additional weapons for their armoury of diagnostic tests; epidemiologists seeking tools to gain seroprevalence data that will inform improved models of the spread of disease; research scientists seeking tools to study the natural history of COVID-19 disease; vaccine developers seeking tools to assess vaccine efficacy in clinical trials; and companies and governments seeking tools to aid return-to-work decision-making. However, much of the local debate to date has centred on questions surrounding whether regulatory approval processes are limiting access to serological tests, and has not paused to consider the intrinsically limiting impact of underlying fundamental biology and immunology on where and how different COVID-19 serological tests can usefully be deployed in the response to the current pandemic. We review, from an immunological perspective, recent experimental evidence on the time-dependency of adaptive immune responses following SARS-CoV-2 infection and the impact of this on the sensitivity and specificity of COVID-19 antibody tests made at different time points post infection. We interpret this scientific evidence in terms of mooted clinical applications for current COVID-19 antibody tests in identifying acute infections, in confirming recent or past infections at the individual and population level, and in detecting re-infection and protective immunity. We conclude with guidance on where current COVID-19 antibody tests can make a genuine impact in the pandemic.

COVID-19 antibody testing: from hype to immunological reality

The potential role for serological tests in the current COVID-19 pandemic has generated very considerable recent interest across many sectors worldwide, inter alia pathologists seeking additional weapons for their armoury of diagnostic tests; epidemiologists seeking tools to gain seroprevalence data that will inform improved models of the spread of disease; research scientists seeking tools to study the natural history of COVID-19 disease; vaccine developers seeking tools to assess vaccine efficacy in clinical trials; and companies and governments seeking tools to aid return-to-work decision-making. However, much of the local debate to date has centred on questions surrounding whether regulatory approval processes are limiting access to serological tests, and has not paused to consider the intrinsically limiting impact of underlying fundamental biology and immunology on where and how different COVID-19 serological tests can usefully be deployed in the response to the current pandemic. We review, from an immunological perspective, recent experimental evidence on the time-dependency of adaptive immune responses following SARS-CoV-2 infection and the impact of this on the sensitivity and specificity of COVID-19 antibody tests made at different time points post infection. We interpret this scientific evidence in terms of mooted clinical applications for current COVID-19 antibody tests in identifying acute infections, in confirming recent or past infections at the individual and population level, and in detecting re-infection and protective immunity. We conclude with guidance on where current COVID-19 antibody tests can make a genuine impact in the pandemic

Human leukocyte antigen (HLA) diversity and clinical applications in South Africa.

The major histocompatibility complex, known as the human leukocyte antigen (HLA) complex in humans, forms an integral component of adaptive T cell immunity by presenting self and non-self peptides to the T cell receptor, thereby allowing clonal expansion of responding peptide-specific CD4+ and CD8+ T cells. HLA likewise forms an integral part of the innate immune response through the binding of killer-cell immunoglobulin-like receptor (KIR) molecules, which regulate the response of natural killer (NK) cells. The HLA complex is found on the short arm of chromosome 6 and is the most polymorphic region in the human genome. Africans are genetically more diverse than other populations; however, information on HLA diversity among southern Africans, including South African populations, is limited. Paucity of African HLA data limits our understanding of disease associations, the ability to identify donor-recipient matches for transplantation and the development of disease-specific vaccines. This review discusses the importance of HLA in the clinical setting in South Africans and highlights how tools such as HLA imputation might augment standard HLA typing methods to increase our understanding of HLA diversity in our populations, which will better inform disease association studies, donor recruitment strategies into bone marrow registries and our understanding of human genetic diversity in South Africa.

Human leukocyte antigen (HLA) diversity and clinical applications in South Africa

The major histocompatibility complex, known as the human leukocyte antigen (HLA) complex in humans, forms an integral component of adaptive T cell immunity by presenting self and non-self peptides to the T cell receptor, thereby allowing clonal expansion of responding peptide-specific CD4+ and CD8+ T cells. HLA likewise forms an integral part of the innate immune response through the binding of killer-cell immunoglobulin-like receptor (KIR) molecules, which regulate the response of natural killer (NK) cells. The HLA complex is found on the short arm of chromosome 6 and is the most polymorphic region in the human genome. Africans are genetically more diverse than other populations; however, information on HLA diversity among southern Africans, including South African populations, is limited. Paucity of African HLA data limits our understanding of disease associations, the ability to identify donor-recipient matches for transplantation and the development of disease-specific vaccines. This review discusses the importance of HLA in the clinical setting in South Africans and highlights how tools such as HLA imputation might augment standard HLA typing methods to increase our understanding of HLA diversity in our populations, which will better inform disease association studies, donor recruitment strategies into bone marrow registries and our understanding of human genetic diversity in South Africa

The intervention process in the European Fans in Training (EuroFIT) trial: a mixed method protocol for evaluation.

BACKGROUND: EuroFIT is a gender-sensitised, health and lifestyle program targeting physical activity, sedentary time and dietary behaviours in men. The delivery of the program in football clubs, led by the clubs' community coaches, is designed to both attract and engage men in lifestyle change through an interest in football or loyalty to the club they support. The EuroFIT program will be evaluated in a multicentre pragmatic randomised controlled trial (RCT), for which ~1000 overweight men, aged 30-65 years, will be recruited in 15 top professional football clubs in the Netherlands, Norway, Portugal and the UK. The process evaluation is designed to investigate how implementation within the RCT is achieved in the various football clubs and countries and the processes through which EuroFIT affects outcomes. METHODS: This mixed methods evaluation is guided by the Medical Research Council (MRC) guidance for conducting process evaluations of complex interventions. Data will be collected in the intervention arm of the EuroFIT trial through: participant questionnaires (n = 500); attendance sheets and coach logs (n = 360); observations of sessions (n = 30); coach questionnaires (n = 30); usage logs from a novel device for self-monitoring physical activity and non-sedentary behaviour (SitFIT); an app-based game to promote social support for physical activity outside program sessions (MatchFIT); interviews with coaches (n = 15); football club representatives (n = 15); and focus groups with participants (n = 30). Written standard operating procedures are used to ensure quality and consistency in data collection and analysis across the participating countries. Data will be analysed thematically within datasets and overall synthesis of findings will address the processes through which the program is implemented in various countries and clubs and through which it affects outcomes, with careful attention to the context of the football club. DISCUSSION: The process evaluation will provide a comprehensive account of what was necessary to implement the EuroFIT program in professional football clubs within a trial setting and how outcomes were affected by the program. This will allow us to re-appraise the program's conceptual base, optimise the program for post-trial implementation and roll out, and offer suggestions for the development and implementation of future initiatives to promote health and wellbeing through professional sports clubs. TRIAL REGISTRATION: ISRCTN81935608 . Registered on 16 June 2015.

Killer-cell Immunoglobulin-like Receptor (KIR) gene profiles modify HIV disease course, not HIV acquisition in South African women.

BACKGROUND: Killer-cell Immunoglobulin-like Receptors (KIR) interact with Human Leukocyte Antigen (HLA) to modify natural killer- and T-cell function. KIR are implicated in HIV acquisition by small studies that have not been widely replicated. A role for KIR in HIV disease progression is more widely replicated and supported by functional studies. METHODS: To assess the role of KIR and KIR ligands in HIV acquisition and disease course, we studied at-risk women in South Africa between 2004-2010. Logistic regression was used for nested case-control analysis of 154 women who acquired vs. 155 who did not acquire HIV, despite high exposure. Linear mixed-effects models were used for cohort analysis of 139 women followed prospectively for a median of 54 months (IQR 31-69) until 2014. RESULTS: Neither KIR repertoires nor HLA alleles were associated with HIV acquisition. However, KIR haplotype BB was associated with lower viral loads (-0.44 log10 copies/ml; SE = 0.18; p = 0.03) and higher CD4+ T-cell counts (+80 cells/µl; SE = 42; p = 0.04). This was largely explained by the protective effect of KIR2DL2/KIR2DS2 on the B haplotype and reciprocal detrimental effect of KIR2DL3 on the A haplotype. CONCLUSIONS: Although neither KIR nor HLA appear to have a role in HIV acquisition, our data are consistent with involvement of KIR2DL2 in HIV control. Additional studies to replicate these findings are indicated.

Frequencies of immune hypersensitivity reaction-associated HLA class I alleles in healthy South African Indian and mixed ancestry populations determined by a novel real-time PCR assay.

We have determined the frequencies of human leucocyte antigen (HLA)-B*57:01, HLA-B*35:05, HLA-C*04 and HLA-C*08 in healthy individuals of South African Indian (SAI) ethnicity (n = 50) and South African mixed (SAM) ancestry (n = 50) using real-time allele-specific polymerase chain reaction (AS-PCR) assay. HLA-B*57:01 associates with immune hypersensitivity reaction (IHR) in individuals exposed to abacavir (ABC), while nevirapine (NVP) IHR associates with HLA-B*35:05, HLA-C*04 and HLA-C*08. Real-time AS-PCR assays typically use less DNA, are more cost-effective and rapid compared with conventional genotyping methods, such as sequence-based typing (SBT). The assay was developed using samples of known HLA class I genotype and subsequently applied to the SAI and SAM samples. HLA-B*57:01 was detected in SAM and SAI populations at frequencies of 8.0% and 12.0%, respectively, while HLA-B*35:05 was not found in SAI individuals, but was present in 6.0% of SAM individuals. HLA-C*04 was detected in 22.0% and 24.0% of SAM and SAI individuals, respectively, while 10.0% and 8.0% of SAM and SAI individuals, respectively, were HLA-C*08 positive. This study reports the development of a novel real-time AS-PCR assay to identify HLA class I alleles associated with ABC and NVP IHR and has established the frequencies of these alleles present in healthy SAI and SAM populations. Using South African demographic data, our hypothetical analysis suggests that a substantial number of individuals would benefit from the assay.

Content-specific fronto-parietal synchronization during visual working memory.

Lateral prefrontal and posterior parietal cortical areas exhibit task-dependent activation during working memory tasks in humans and monkeys. Neurons in these regions become synchronized during attention-demanding tasks, but the contribution of these interactions to working memory is largely unknown. Using simultaneous recordings of neural activity from multiple areas in both regions, we find widespread, task-dependent, and content-specific synchronization of activity across the fronto-parietal network during visual working memory. The patterns of synchronization are prevalent among stimulus-selective neurons and are governed by influences arising in parietal cortex. These results indicate that short-term memories are represented by large-scale patterns of synchronized activity across the fronto-parietal network.

Temporal association of HLA-B*81:01- and HLA-B*39:10-mediated HIV-1 p24 sequence evolution with disease progression.

HLA-B*81:01 and HLA-B*39:10 alleles have been associated with viremic control in HIV-1 subtype C infection. Both alleles restrict the TL9 epitope in p24 Gag, and cytotoxic-T-lymphocyte (CTL)-mediated escape mutations in this epitope have been associated with an in vitro fitness cost to the virus. We investigated the timing and impact of mutations in the TL9 epitope on disease progression in five B*81:01- and two B*39:10-positive subtype C-infected individuals. Whereas both B*39:10 participants sampled at 2 months postinfection had viruses with mutations in the TL9 epitope, in three of the five (3/5) B*81:01 participants, TL9 escape mutations were only detected 10 months after infection, taking an additional 10 to 15 months to reach fixation. In the two remaining B*81:01 individuals, one carried a TL9 escape variant at 2 weeks postinfection, whereas no escape mutations were detected in the virus from the other participant for up to 33 months postinfection, despite CTL targeting of the epitope. In all participants, escape mutations in TL9 were linked to coevolving residues in the region of Gag known to be associated with host tropism. Late escape in TL9, together with coevolution of putative compensatory mutations, coincided with a spontaneous increase in viral loads in two individuals who were otherwise controlling the infection. These results provide in vivo evidence of the detrimental impact of B*81:01-mediated viral evolution, in a single Gag p24 epitope, on the control of viremia.

Passively transmitted gp41 antibodies in babies born from HIV-1 subtype C-seropositive women: correlation between fine specificity and protection.

HIV-exposed, uninfected (EUN) babies born to HIV-infected mothers are examples of natural resistance to HIV infection. In this study, we evaluated the titer and neutralizing potential of gp41-specific maternal antibodies and their correlation with HIV transmission in HIV-infected mother-child pairs. Specific gp41-binding and -neutralizing antibodies were determined in a cohort of 74 first-time mother-child pairs, of whom 40 mothers were infected with HIV subtype C. Within the infected mother cohort, 16 babies were born infected and 24 were PCR negative and uninfected at birth (i.e., exposed but uninfected). Thirty-four HIV-uninfected and HIV-unexposed mother-child pairs were included as controls. All HIV-positive mothers and their newborns showed high IgG titers to linear epitopes within the HR1 region and to the membrane-proximal (MPER) domain of gp41; most sera also recognized the disulfide loop immunodominant epitope (IDE). Antibody titers to the gp41 epitopes were significantly lower in nontransmitting mothers (P < 0.01) and in the EUN babies (P < 0.005) than in HIV-positive mother-child pairs. Three domains of gp41, HR1, IDE, and MPER, elicited antibodies that were effectively transmitted to EUN babies. Moreover, in EUN babies, epitopes overlapping the 2F5 epitope (ELDKWAS), but not the 4E10 epitope, were neutralization targets in two out of four viruses tested. Our findings highlight important epitopes in gp41 that appear to be associated with exposure without infection and would be important to consider for vaccine design.

Killer-cell immunoglobulin-like receptor genotyping and HLA killer-cell immunoglobulin-like receptor-ligand identification by real-time polymerase chain reaction.

The effector function of natural killer (NK) cells is modulated by surface expression of a range of killer-cell immunoglobulin-like receptors (KIRs) that interact with human leukocyte antigen (HLA) class I ligands. We describe the use of real-time polymerase chain reaction (PCR) assays that allow easy and quick detection of 16 KIR genes and the presence/absence of KIR-ligands based on allelic discrimination at codon 80 in the HLA-A/B Bw4 and HLA-C C1/C2 genes. These methods overcome the tedious and expensive nature of conventional KIR genotyping and HLA class I typing using sequence-specific primer (SSP) PCR, sequence-specific oligonucleotide (SSO) hybridization or sequence-based typing (SBT). Using these two cost-effective assays, we measured the frequencies of KIRs, KIR-ligands and KIR/KIR-ligand pairs in a cohort of Black women recruited in South Africa.

Virological and immunological factors associated with HIV-1 differential disease progression in HLA-B 58:01-positive individuals.

Molecular epidemiology studies have identified HLA-B 58:01 as a protective HIV allele. However, not all B 58:01-expressing persons exhibit slow HIV disease progression. We followed six HLA-B 58:01-positive, HIV subtype C-infected individuals for up to 31 months from the onset of infection and observed substantial variability in their clinical progression despite comparable total breadths of T cell responses. We therefore investigated additional immunological and virological factors that could explain their different disease trajectories. Cytotoxic T-lymphocyte (CTL) responses during acute infection predominantly targeted the TW10 and KF9 epitopes in p24(Gag) and Nef, respectively. Failure to target the TW10 epitope in one B 58:01-positive individual was associated with low CD4(+) counts and rapid disease progression. Among those targeting TW10, escape mutations arose within 2 to 15 weeks of infection. Rapid escape was associated with preexisting compensatory mutations in the transmitted viruses, which were present at a high frequency (69%) in the study population. At 1 year postinfection, B 58:01-positive individuals who targeted and developed escape mutations in the TW10 epitope (n = 5) retained significantly higher CD4(+) counts (P = 0.04), but not lower viral loads, than non-B 58:01-positive individuals (n = 17). The high population-level frequency of these compensatory mutations may be limiting the protective effect of the B 58:01 allele.

The RET/PTC3 oncogene activates classical NF-κB by stabilizing NIK.

The oncogenic fusion protein RET/PTC3 (RP3) that is expressed in papillary thyroid carcinoma (PTC) and thyroid epithelia in Hashimoto's thyroiditis activates nuclear factor-kappa B (NF-κB) and induces pro-inflammatory gene expression; however, the mechanism of this activation is unknown. To address this, we expressed RP3 in murine embryonic fibroblasts (MEFs) lacking key classical and noncanonical NF-κB signaling components. In wild-type MEFs, RP3 upregulated CCL2, CXCL1, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor expression and activated classical but not noncanonical NF-κB. RP3-activated NF-κB in IκB kinase (IKK)ß(-/-) MEFs but not IKKα- or NF-κB essential modulator (NEMO)-deficient cells and activation was inhibited by a peptide that blocks NEMO binding to the IKKs. RP3 increased the levels of NF-κB-inducing kinase (NIK) and did not activate NF-κB in NIK-deficient MEFs. Notably, NIK stabilization was not accompanied by TRAF3 degradation demonstrating that RP3 disrupts normal basal NIK regulation. Dominant-negative NIK blocked RP3-induced NF-κB activation and an RP3 signaling mutant (RP3(Y588F)) did not stabilize NIK. Finally, examination of PTC specimens revealed strong positive staining for NIK. We therefore conclude that RP3 activates classical NF-κB via NIK, NEMO and IKKα. Importantly, our findings reveal a novel mechanism for oncogene-induced NF-κB activation via stabilization of NIK.

Adaptive changes in HIV-1 subtype C proteins during early infection are driven by changes in HLA-associated immune pressure.

It is unresolved whether recently transmitted human immunodeficiency viruses (HIV) have genetic features that specifically favour their transmissibility. To identify potential "transmission signatures", we compared 20 full-length HIV-1 subtype C genomes from primary infections, with 66 sampled from ethnically and geographically matched individuals with chronic infections. Controlling for recombination and phylogenetic relatedness, we identified 39 sites at which amino acid frequency spectra differed significantly between groups. These sites were predominantly located within Env, Pol and Gag (14/39, 9/39 and 6/39 respectively) and were significantly clustered (33/39) within known immunoreactive peptides. Within 6 months of infection, we detected reversion-to-consensus mutations at 14 sites and potential CTL escape mutations at seven. Here we provide evidence that frequent reversion mutations probably allows the virus to recover replicative fitness which, together with immune escape driven by the HLA alleles of the new hosts, differentiate sequences from chronic infections from those sampled shortly after transmission.

Cortical vascular canals in human mandible and other bones.

The human mandible is highly mineralized. We hypothesized that this is related to the local vascularity of the bone. This could not be examined directly, but, as a surrogate, intracortical vascular canal spaces of the human mandible were studied so that we could determine possible relationships with age, gender, location, dental status, and tissue mineralization. Canal numbers, area, and volume fraction were calculated from quantitative backscattered electron images of human mandibles aged 16-96 years. Data were compared with calvaria, maxilla, lumbar vertebra, femoral neck, and iliac crest. In the mandible, the buccal aspect of the midline was the most porous, the canals being larger and more numerous. The cortical porosity in the posterior of partially dentate mandibles was significantly greater than that of either dentate or edentate mandibles, and there was a significant increase in the size of canals in the mandible with increasing age. Female mandibles had more porous cortices. No relationship was found between cortical porosity and the degree of bone mineralization.

Magmatic and crustal differentiation history of granitic rocks from Hf-O isotopes in zircon.

Granitic plutonism is the principal agent of crustal differentiation, but linking granite emplacement to crust formation requires knowledge of the magmatic evolution, which is notoriously difficult to reconstruct from bulk rock compositions. We unlocked the plutonic archive through hafnium (Hf) and oxygen (O) isotope analysis of zoned zircon crystals from the classic hornblende-bearing (I-type) granites of eastern Australia. This granite type forms by the reworking of sedimentary materials by mantle-like magmas instead of by remelting ancient metamorphosed igneous rocks as widely believed. I-type magmatism thus drives the coupled growth and differentiation of continental crust.

Dynamic HIV/AIDS parameter estimation with application to a vaccine readiness study in southern Africa.

This paper proposes a procedure of parameter estimation for all parameters of the three-dimensional HIV model. The least square based procedure uses standard optimization routines to allow parameter extraction for individual patients. It is shown how additional information from outside a measurement dataset can be included in the estimation routine to increase the reliability and accuracy of parameter estimates. A dataset from 44 patients of Southern Africa is analyzed to find the set point and the time until set point for these patients together with an estimate of the model parameters with confidence intervals for the cohort. The procedure is also applied to a long-term dataset of the HIV/AIDS progression to find possible variations in parameters.

Conserved domains of subtype C nef from South African HIV type 1-infected individuals include cytotoxic T lymphocyte epitope-rich regions.

We have characterized 43 nef sequences from subtype C HIV-1-infected South Africans and compared deduced amino acid sequences with other subtypes to identify areas of conservation. Our Nef amino acid sequences were aligned with a consensus subtype B, HXB2 reference strain and a consensus subtype C sequence. All were found to be highly homologous to subtype B in the central region of Nef, but more variable at the N and C termini of the molecule. Alignment of a consensus amino acid sequence generated from South African subtype C Nef with subtypes A, B, and D underscores cross-clade conservation in the central domain of the molecule. This domain is also rich in previously described cytotoxic T lymphocyte (CTL) epitopes that are restricted by commonly found HLA molecules in the South African population.

Rethinking globally relevant vaccine strategies to human immunodeficiency virus type-1.

According to the latest UNAIDS figures for 1999 there were an estimated 30.6 million people living with HIV-1, with 16,000 new HIV infections per day. The only global strategy of combating new HIV infections is to make a vaccine that is affordable to developing countries, where greater than 90% of new infections occur, and that has enough efficacy to interrupt high rates of transmission. This review critically examines: 1) important immune parameters that should be considered which will allow an understanding of preventative vaccine design and 2) the mechanisms underlying immune destruction during HIV-1 infection that will facilitate design of therapeutic vaccines. A realistic goal of a preventative vaccine is to elicit protective immune responses in vaccinees that would prevent HIV-1 from replicating extensively in the host. Components of protective immunity are thought to include neutralizing antibodies (NAB) and cytotoxic T lymphocytes (CTL). Rethinking vaccine strategies has to take into account that HIV-1 vaccines must elicit primary cellular and humoral immunity via dendritic cell and Langerhan cell priming. It is only under these conditions that boosting immunity with subsequent vaccinations will allow high enough CTL effector cells and NAB titres to impede or to prevent HIV-1 replication. Success of therapeutic vaccine strategies, has to take into consideration the pathology of persistent immune stimulation by chronic HIV-1 infection. To re-stimulate immunity and re-direct immune responses, chronic immune stimulation by HIV-1 has to be alleviated by reducing high levels of viral antigen presentation by suppressing virus with antiretroviral agents. Such treatment courses may only have to be transient, long enough for immunity to respond to an immunogenic stimulus. Short-course drug therapy may then be an affordable option for many countries already carrying a high burden of HIV-1/AIDS.