Immune reconstitution sarcoidosis presenting with hypercalcaemia and renal failure in HIV infection

An HIV-positive white man developed hypercalcaemia and renal failure 15 months after starting highly active antiretroviral therapy. Investigations showed systemic sarcoidosis affecting parotids, skin and kidneys. This presentation was thought to be a manifestation of immune reconstitution inflammatory syndrome, and the patient was successfully treated with corticosteroid therapy.

HIV infection of dendritic cells subverts the IFN induction pathway via IRF-1 and inhibits type 1 IFN production

Many viruses have developed mechanisms to evade the IFN response. Here, HIV-1 was shown to induce a distinct subset of IFN-stimulated genes (ISGs) in monocyte-derived dendritic cells (DCs), without detectable type I or II IFN. These ISGs all contained an IFN regulatory factor 1 (IRF-1) binding site in their promoters, and their expression was shown to be driven by IRF-1, indicating this subset was induced directly by viral infection by IRF-1. IRF-1 and -7 protein expression was enriched in HIV p24 antigen-positive DCs. A HIV deletion mutant with the IRF-1 binding site deleted from the long terminal repeat showed reduced growth kinetics. Early and persistent induction of IRF-1 was coupled with sequential transient up-regulation of its 2 inhibitors, IRF-8, followed by IRF-2, suggesting a mechanism for IFN inhibition. HIV-1 mutants with Vpr deleted induced IFN, showing that Vpr is inhibitory. However, HIV IFN inhibition was mediated by failure of IRF-3 activation rather than by its degradation, as in T cells. In contrast, herpes simplex virus type 2 markedly induced IFNβ and a broader range of ISGs to higher levels, supporting the hypothesis that HIV-1 specifically manipulates the induction of IFN and ISGs to enhance its noncytopathic replication in DCs.

Intracellular dynamics of HIV infection

Early studies of HIV infection dynamics suggested that virus-producing HIV-infected cells had an average half-life of approximately 1 day. However, whether this average behavior is reflective of the dynamics of individual infected cells is unclear. Here, we use HIV-enhanced green fluorescent protein (EGFP) constructs and flow cytometry sorting to explore the dynamics of cell infection, viral protein production, and cell death in vitro. By following the numbers of productively infected cells expressing EGFP over time, we show that infected cell death slows down over time. Although infected cell death in vivo could be very different, our results suggest that the constant decay of cell numbers observed in vivo during antiretroviral treatment could reflect a balance of cell death and delayed viral protein production. We observe no correlation between viral protein production and death rate of productively infected cells, showing that viral protein production is not likely to be the sole determinant of the death of HIV-infected cells. Finally, we show that all observed features can be reproduced by a simple model in which infected cells have broad distributions of productive life spans, times to start viral protein production, and viral protein production rates. This broad spectrum of the level and timing of viral protein production provides new insights into the behavior and characteristics of HIV-infected cells.

X4 and R5 HIV-1 have distinct post-entry requirements for uracil DNA glycosylase during infection of primary cells

It has been assumed that R5 and X4 HIV utilize similar strategies to support viral cDNA synthesis post viral entry. In this study, we provide evidence to show that R5 and X4 HIV have distinct requirements for host cell uracil DNA glycosylase (UNG2) during the early stage of infection. UNG2 has been previously implicated in HIV infection, but its precise role remains controversial. In this study we show that, although UNG2 is highly expressed in different cell lines, UNG2 levels are low in the natural host cells of HIV. Short interfering RNA knockdown of endogenous UNG2 in primary cells showed that UNG2 is required for R5 but not X4 HIV infection and that this requirement is bypassed when HIV enters the target cell via vesicular stomatitis virus envelope-glycoprotein-mediated endocytosis. We also show that short interfering RNA knockdown of UNG2 in virus-producing primary cells leads to defective R5 HIV virions that are unable to complete viral cDNA synthesis. Quantitative PCR analysis revealed that endogenous UNG2 levels are transiently up-regulated post HIV infection, and this increase in UNG2 mRNA is ∼10–20 times higher in R5 versus X4 HIV-infected cells. Our data show that both virion-associated UNG2 and HIV infection-induced UNG2 expression are critical for reverse transcription during R5 but not X4 HIV infection. More importantly, we have made the novel observation that R5 and X4 HIV have distinct host cell factor requirements and differential capacities to induce gene expression during the early stages of infection. These differences may result from activation of distinct signaling cascades and/or infection of divergent T-lymphocyte subpopulations.

Unrealistic optimism about becoming infected with HIV: different causes in different populations

People tend to believe that their chance of experiencing undesirable events is lower and their chance of experiencing desirable events is higher than that of the average person like them. Two explanatory models of such 'unrealistic optimism' (UO) have been proposed: While the motivational account holds that UO serves the function of bringing comfort, the cognitive account holds that UO serves no particular function, being simply a by-product of normal cognitive strategies. UO for HIV infection was studied in samples of uninfected students (Study 1, n = 68) and gay men (Study 2, n = 63). In each case, participants rated either their relative likelihood of becoming infected (negative valence condition) or their relative likelihood of remaining uninfected (positive valence condition). As predicted, in Study 1 UO was greater where valence was negative and in Study 2 valence had no effect. The findings suggest that the students' UO is better explained by the motivational account, while the gay men's UO is better explained by the cognitive account. Implications for AIDS education are discussed.

A method for the quantitative analysis of the layering of HIV-related stigma

HIV-related stigma is regarded as one of the major barriers in the development of effective prevention and care programs; but the stigma associated with HIV stigma is not a singular entity. The stigma of the infection is layered with other stigmas, such as those associated with the routes of transmission (e.g., sex work and injecting drug use) and personal characteristics (e.g., race, religion, ethnicity and gender). In developing programs and policies to overcome HIV-related stigma, cognisance needs to be taken of all the sources of stigma, and how they may interact. A novel method is described for examining the layers of HIV/AIDS-related stigma, and secondary data are adapted to illustrate this. The importance of understanding the layering of stigma for the development of effective interventions is also discussed.

HIV discrimination : integrating the results from a six-country situational anaylsis in the Asia Pacific

The findings of the six independent studies on institutional forms of HIV discrimination in the Asia Pacific presented in this Special Issue of AIDS Care are integrated. At first glance, the general pattern of the results across the study sites suggests that discrimination is most pertinent in the domain of 'practice' rather than in the domains of law or institutional policy. On closer analysis, however, utilising the qualitative data, this conclusion does not take sufficient account of the cultural context within which the interpersonal interaction (practice) between the health carers and people living with HIV/AIDS occurs. Limitations on the use of anti-discrimination legislations and protective written policies for reducing discrimination in these contexts are discussed. The need for alternative approaches to thinking about discrimination intervention is raised and this is done through a consideration of the strategy of universal precautions.

Institutional and structural forms of HIV-related discrimination in health care : a study set in Beijing

This paper presents key findings of a situational analysis of institutional and structural levels of HIV/AIDS-related discrimination in Beijing, China, with a focus on the area of health care. Initially slow to respond to the presence of HIV, China has altered its approach and enacted strict legislative protection for people living with HIV/AIDS (PLWHA). In order to determine whether this has altered discrimination against PLWHA, this study examined existing legislation and policy, and interviewed key informants working in health care and PLWHA. The overall findings revealed that discrimination in its many forms continued to occur in practice despite China's generally strong legislative protection, and it is the actual practice that is hindering PLWHAs' access to health services. A number of legislative and policy gaps that allow discrimination to occur in practice were also identified and discussed. The paper concludes with a call to rectify specific gaps between legislation, policy and practice. An understanding of the underlying factors that drive discrimination will also be necessary for effective strategic interventions to be developed and implemented.

An Asia Pacific six-country study on HIV-related discrimination : introduction

This paper outlines a six-country study of institutionalised forms of HIV/AIDS-related discrimination in the Asia-Pacific region. Although recognised as a barrier to disease prevention and treatment, very limited data are available on the effects of institutionalised HIV-related stigma and discrimination. Understanding the forms of discrimination within the institutions where they occur is the first step to identifying effective ways of promoting compassionate, non-discriminatory treatment of PLWHA. Thus, the goal of this research project was to document institutional discrimination against PLWHA, as guided by the UNAIDS Protocol for the Identification of Discrimination Against People Living with HIV (2000), in six Asian countries: India, Thailand, Philippines, China, Vietnam and Indonesia. As a precursor to the six individual studies, this paper provides a brief overview of the literature on HIV discrimination, and then describes the UNAIDS Protocol and the shared methodological considerations relevant to all of the study sites. Commonalities in sampling, procedures and analysis are also discussed.

Markers and risk factors for HCV, HBV and HIV in a network of injecting drug users in Melbourne

Background and aims: Current injecting drug users (IDU) in major street drug markets within greater Melbourne were recruited to a longitudinal study on blood borne viruses. Here we investigated risk factors for hepatitis C virus (HCV), hepatitis B virus (HBV) and HIV infection in these IDU at the time of their recruitment.

Methods : Three hundred and eighty-two IDU completed detailed questionnaires on their drug use and risk behaviours, and provided blood samples for serology testing. These data were analysed using univariate and multivariate techniques.

Results : The overall prevalence of exposure to HCV, HBV and HIV was estimated at 70%, 34% and <1%, respectively. Independent predictors of HCV exposure were history of imprisonment (RR 1.34, 95% CI 1.19–1.52), use of someone else's needle or syringe (RR 1.23, 95% CI 1.07–1.42), >7.6 years length of time injecting (RR 1.21, 95% CI 1.07–1.37), and originating from Vietnam (RR 1.12, 95% CI 1.07–1.18). Independent predictors of HBV exposure were HCV exposure (RR 2.15, 95% CI 1.35–3.43), >7.6 years length of time injecting (RR 1.57, 95% CI 1.17–2.13) and originating from outside Australia (RR 1.60, 95% CI 1.22–2.10). Neither prison- nor community-applied tattoos predicted HCV or HBV exposure. Up to 31% of IDU who injected for 1 year or less were HCV antibody positive, as were 53% of those who injected for 2 years or less.

Conclusions : Ongoing engagement with young IDU, through the provision of harm reduction education and resources, is critical if we are to address blood borne viral infections and other health and social harms associated with injecting drug use.

Cost-effectiveness of adult circumcision in a resource-rich setting for HIV prevention among men who have sex with men

Background.  We examined the effects and cost‐effectiveness of 4 strategies of circumcision in a resource‐rich setting (Australia) in a population of men who have sex with men (MSM).

Method.  We created a dynamic mathematical transmission model and performed an economic analysis to estimate the costs, outcomes, and cost‐effectiveness of different strategies, compared with those of the status quo. Strategies included circumcision of all MSM at age 18 years, circumcision of all MSM aged 35–44 years, circumcision of all insertive MSM aged 18 years, and circumcision of all MSM aged 18 years . All costs are reported in US dollars, with a cost‐effectiveness threshold of $42,000 per quality‐adjusted life‐year.

Results.  We find that 2%–5% of human immunodeficiency virus (HIV) infections would be averted per year, with initial costs ranging from $3.6 million to $95.1 million, depending on the strategy. The number of circumcisions needed to prevent 1 HIV infection would range from 118 through 338. Circumcision of predominately insertive MSM would save $21.7 million over 25 years with a $62.2 million investment. Strategies to circumcise 100% of all MSM and to circumcise MSM aged 35–44 years would be cost‐effective; the latter would require a smaller investment. The least cost‐effective approach is circumcision of young MSM close to their sexual debut. Results are very sensitive to assumptions about the cost of circumcision, the efficacy of circumcision, sexual preferences, and behavioral disinhibition.

Conclusions.  Circumcision of adult MSM may be cost‐effective in this resource‐rich setting. However, the intervention costs are high relative to the costs spent on other HIV prevention programs.

Reconstructing the incidence of human immunodeficiency virus (HIV) in Hong Kong by using data from HIV positive tests and diagnoses of acquired immune deficiency syndrome

The human immunodeficiency virus–acquired immune deficiency syndrome (HIV–AIDS) epidemic in Hong Kong has been under surveillance in the form of voluntary reporting since 1984. However, there has been little discussion or research on the reconstruction of the HIV incidence curve. This paper is the first to use a modified back-projection method to estimate the incidence of HIV in Hong Kong on the basis of the number of positive HIV tests only. The model proposed has several advantages over the original back-projection method based on AIDS data only. First, not all HIV-infected individuals will develop AIDS by the time of analysis, but some of them may undertake an HIV test; therefore, the HIV data set contains more information than the AIDS data set. Second, the HIV diagnosis curve usually has a smoother pattern than the AIDS diagnosis curve, as it is not affected by redefinition of AIDS. Third, the time to positive HIV diagnosis is unlikely to be affected by treatment effects, as it is unlikely that an individual receives medication before the diagnosis of HIV. Fourth, the induction period from HIV infection to the first HIV positive test is usually shorter than the incubation period which is from HIV infection to diagnosis of AIDS. With a shorter induction period, more information becomes available for estimating the HIV incidence curve. Finally, this method requires the number of positive HIV diagnoses only, which is readily available from HIV–AIDS surveillance systems in many countries. It is estimated that, in Hong Kong, the cumulative number of HIV infections during the period 1979–2000 is about 2600, whereas an estimate based only on AIDS data seems to give an underestimate.

Fifteen to twenty percent of HIV substitution mutations are associated with recombination

HIV undergoes high rates of mutation and recombination during reverse transcription, but it is not known whether these events occur independently or are linked mechanistically. Here we used a system of silent marker mutations in HIV and a single round of infection in primary T lymphocytes combined with a high-throughput sequencing and mathematical modeling approach to directly estimate the viral recombination and mutation rates. From >7 million nucleotides (nt) of sequences from HIV infection, we observed 4,801 recombination events and 859 substitution mutations (≈1.51 and 0.12 events per 1,000 nt, respectively). We used experimental controls to account for PCR-induced and transfection-induced recombination and sequencing error. We found that the single-cycle virus-induced mutation rate is 4.6 × 10(-5) mutations per nt after correction. By sorting of our data into recombined and nonrecombined sequences, we found a significantly higher mutation rate in recombined regions (P = 0.003 by Fisher's exact test). We used a permutation approach to eliminate a number of potential confounding factors and confirm that mutation occurs around the site of recombination and is not simply colocated in the genome. By comparing mutation rates in recombined and nonrecombined regions, we found that recombination-associated mutations account for 15 to 20% of all mutations occurring during reverse transcription.

Estimating the in-vivo HIV template switching and recombination rate

BACKGROUND: HIV recombination has been estimated in vitro using a variety of approaches, and shows a high rate of template switching per reverse transcription event. In-vivo studies of recombination generally measure the accumulation of recombinant strains over time, and thus do not directly estimate a comparable template switching rate. METHOD: To examine whether the estimated in-vitro template switching rate is representative of the rate that occurs during HIV infection in vivo, we adopted a novel approach, analysing single genome sequences from early founder viruses to study the in-vivo template switching rate in the env region of HIV. RESULTS: We estimated the in-vivo per cycle template switching rate to be between 0.5 and 1.5/1000 nt, or approximately 5-14 recombination events over the length of the HIV genome. CONCLUSION: The in-vivo estimated template switching rate is close to the in-vitro estimated rate found in primary T lymphocytes but not macrophages, which is consistent with the majority of HIV infection occurring in T lymphocytes.