Central memory CD4+ T cell responses in chronic HIV infection are not restored by antiretroviral therapy

A strong CD4(+) T cell response has been correlated with better control of HIV infection. However, the effect of HIV on the maintenance of Ag-specific memory CD4(+) T cells is not fully understood. We characterized the function and phenotype of memory CD4(+) T cells generated by mumps and influenza A or B viruses in HIV-infected individuals receiving highly active antiretroviral therapy (n = 21), HIV-infected long-term nonprogressors (n = 10), and HIV-seronegative volunteers (n = 10). We observed significantly decreased proliferation of the Ag-specific central memory CD4(+) T cell population (CD28(+)/CCR7(+)/CD45RA(-)) in the antiretroviral treated HIV-infected individuals compared with the seronegative controls. Restored CD4(+) T cell count and decreased HIV viral load while on highly active antiretroviral therapy did not result in increased proliferation, whereas nadir CD4(+) T cell count predicted the presence of Ag-specific proliferation. Our results indicate that HIV infection leads to impaired maintenance of virus-induced or vaccine-generated central memory CD4(+) T cells that is not restored by HAART.     

Development and validation of decision rules to guide frequency of monitoring CD4 cell count in HIV-1 infection before starting antiretroviral therapy

Background

Although CD4 cell count monitoring is used to decide when to start antiretroviral therapy in patients with HIV-1 infection, there are no evidence-based recommendations regarding its optimal frequency. It is common practice to monitor every 3 to 6 months, often coupled with viral load monitoring. We developed rules to guide frequency of CD4 cell count monitoring in HIV infection before starting antiretroviral therapy, which we validated retrospectively in patients from the Swiss HIV Cohort Study.

Methodology/Principal Findings

We built up two prediction rules (“Snap-shot rule” for a single sample and “Track-shot rule” for multiple determinations) based on a systematic review of published longitudinal analyses of CD4 cell count trajectories. We applied the rules in 2608 untreated patients to classify their 18 061 CD4 counts as either justifiable or superfluous, according to their prior ≥5% or <5% chance of meeting predetermined thresholds for starting treatment. The percentage of measurements that both rules falsely deemed superfluous never exceeded 5%. Superfluous CD4 determinations represented 4%, 11%, and 39% of all actual determinations for treatment thresholds of 500, 350, and 200×10⁶/L, respectively. The Track-shot rule was only marginally superior to the Snap-shot rule. Both rules lose usefulness for CD4 counts coming near to treatment threshold.

Conclusions/Significance

Frequent CD4 count monitoring of patients with CD4 counts well above the threshold for initiating therapy is unlikely to identify patients who require therapy. It appears sufficient to measure CD4 cell count 1 year after a count >650 for a threshold of 200, >900 for 350, or >1150 for 500×10⁶/L, respectively. When CD4 counts fall below these limits, increased monitoring frequency becomes advisable. These rules offer guidance for efficient CD4 monitoring, particularly in resource-limited settings.     

HIV infected CD4+ T cell clones are more stable than uninfected clones during long-term antiretroviral therapy

Although combination antiretroviral therapy (ART) blocks HIV replication, it is not curative because infected CD4+ T cells that carry intact, infectious proviruses persist. Understanding the behavior of clones of infected T cells is important for understanding the stability of the reservoir; however, the stabilities of clones of infected T cells in persons on long-term ART are not well defined. We determined the relative stabilities of clones of infected and uninfected CD4+ T cells over time intervals of one to four years in three individuals who had been on ART for 9–19 years. The largest clones of uninfected T cells were larger than the largest clones of infected T cells. Clones of infected CD4+ T cells were more stable than clones of uninfected CD4+ T cells of a similar size. Individual clones of CD4+ T cells carrying intact, infectious proviruses can expand, contract, or remain stable over time.     

Use of CD4 lymphocyte count to predict long-term survival free of AIDS after HIV infection.

OBJECTIVE--To estimate the probability of remaining free of AIDS for up to 25 years after infection with HIV by extrapolation of changes in CD4 lymphocyte count. DESIGN--Cohort study of subjects followed from time of HIV seroconversion until 1 January 1993. Creation of model by using extrapolated linear regression slopes of CD4 count to predict development of AIDS after 1993. SETTING--Regional haemophilia centre in teaching hospital. SUBJECTS--111 men with haemophilia infected with HIV during 1979-85. Median length of follow up 10.1 years, median number of CD4 counts 17. The model was not fitted for three men because only one CD4 measurement was available. MAIN OUTCOME MEASURES--Development of AIDS. INTERVENTIONS--From 1989 prophylaxis against candida and Pneumocystis carinii pneumonia and antiretroviral drugs when CD4 count fell below 200 x 10(6)/l. RESULTS--44 men developed AIDS up to 1 January 1993. When AIDS was defined as a CD4 count of 50 x 10(6)/l the model predicted that 25% (95% confidence interval 16% to 34%) would survive for 20 years after seroconversion and 18% (11% to 25%) for 25 years. Changing the CD4 count at which AIDS was assumed to occur did not alter the results. Younger patients had a higher chance of 20 year survival than older patients (32% (12% to 52%) for those aged < 15, 26% (14% to 38%) for those aged 15-29, and 15% (0% to 31%) for those aged > or = 30). CONCLUSIONS--These results suggest that even with currently available treatment up to a quarter of patients with HIV infection will survive for 20 years after seroconversion without developing AIDS.     

BD Biosciences contributions in CD4 counting and immune status for HIV/AIDS

BD Biosciences is a leader in the use of flow cytometry for determining immune system status and for counting CD4 cells in patients with human immunodeficiency virus (HIV) infection. The company has gained this position through many years of basic research and product development in immunology and cell biology, dye chemistry, immunoassays, instrumentation, and software. Some of the highlights of these developments and their historical perspective are described in this review.     

Impact of Community-Based HIV/AIDS Treatment on Household Incomes in Uganda

Though health benefits to households in developing countries from antiretroviral treatment (ART) programs are widely reported in the literature, specific estimates regarding impacts of treatments on household incomes are rare. This type of information is important to governments and donors, as it is an indication of returns to their ART investments, and to better understand the role of HIV/AIDS in development. The objective of this study is to estimate the impact of a community-based ART program on household incomes in a previously underserved rural region of Uganda. A community-based ART program, based largely on labor contributions from community volunteers, was implemented and evaluated. All households with HIV/AIDS patients enrolled in the treatment programme (n = 134 households) were surveyed five times; once at the beginning of the treatment and every three months thereafter for a period of one year. Data were collected on household income from cash earnings and value of own production. The analysis, using ordinary least squares and quantile regressions, identifies the impact of the ART program on household incomes over the first year of the treatment, while controlling for heterogeneity in household characteristics and temporal changes. As a result of the treatment, health conditions of virtually all patients improved, and household incomes increased by approximately 30% to 40%, regardless of household income quantile. These increases in income, however, varied significantly depending on socio-demographic and socio-economic control variables. Overall, results show large and significant impacts of the ART program on household incomes, suggesting large returns to public investments in ART, and that treating HIV/AIDS is an important precondition for development. Moreover, development programs that invest in human capital and build wealth are important complements that can increase the returns to ART programs.     

Failure time analysis of HIV vaccine effects on viral load and antiretroviral therapy initiation

The world's first efficacy trial of a preventive HIV vaccine was completed in 2003. Study participants who became HIV infected were followed for 2 years and monitored for HIV viral load and initiation of antiretroviral therapy (ART). In order to determine if vaccination may have altered HIV progression in persons who acquired HIV, a pre-specified objective was to compare the time until a composite endpoint between the vaccine and placebo arms, where the composite endpoint is the first event of ART initiation or viral failure (HIV viral load exceeds a threshold x(vl) copies/ml). Specifically, with vaccine efficacy, VE(tau, x(vl)), defined as one minus the ratio (vaccine/placebo) of the cumulative probability of the composite endpoint (with failure threshold x(vl)) occurring by tau months, the aim was to estimate the four parameters {VE(tau, x(vl)): x(vl) is an element of {1500, 10,000, 20,000, 55,000} copies/ml} with simultaneous 95% confidence bands. A Gaussian multipliers simulation method is devised for constructing confidence bands for VE(tau, x(vl)) with x(vl) spanning multiple discrete values or a continuous range. The new method is evaluated in simulations and is applied to the vaccine trial data set.     

Cumulative viral load and virologic decay patterns after antiretroviral therapy in HIV-infected subjects influence CD4 recovery and AIDS

Background

The impact of viral load (VL) decay and cumulative VL on CD4 recovery and AIDS after highly-active antiretroviral therapy (HAART) is unknown.

Methods and Findings

Three virologic kinetic parameters (first year and overall exponential VL decay constants, and first year VL slope) and cumulative VL during HAART were estimated for 2,278 patients who initiated HAART in the U.S. Military HIV Natural History Study. CD4 and VL trajectories were computed using linear and nonlinear Generalized Estimating Equations models. Multivariate Poisson and linear regression models were used to determine associations of VL parameters with CD4 recovery, adjusted for factors known to correlate with immune recovery. Cumulative VL higher than the sample median was independently associated with an increased risk of AIDS (relative risk 2.38, 95% confidence interval 1.56–3.62, p<0.001). Among patients with VL suppression, first year VL decay and slope were independent predictors of early CD4 recovery (p = 0.001) and overall gain (p<0.05). Despite VL suppression, those with slow decay during the first year of HAART as well as during the entire therapy period (overall), in general, gained less CD4 cells compared to the other subjects (133 vs. 195.4 cells/µL; p = 0.001) even after adjusting for potential confounders.

Conclusions

In a cohort with free access to healthcare, independent of established predictors of AIDS and CD4 recovery during HAART, cumulative VL and virologic decay patterns were associated with AIDS and distinct aspects of CD4 reconstitution.     

Effect of community-led delivery of HIV self-testing on HIV testing and antiretroviral therapy initiation in Malawi: A cluster-randomised trial

BackgroundUndiagnosed HIV infection remains substantial in key population subgroups including adolescents, older adults, and men, driving ongoing transmission in sub-Saharan Africa. We evaluated the impact, safety, and costs of community-led delivery of HIV self-testing (HIVST), aiming to increase HIV testing in underserved subgroups and stimulate demand for antiretroviral therapy (ART).Methods and findingsThis cluster-randomised trial, conducted between October 2018 and July 2019, used restricted randomisation (1:1) to allocate 30 group village head clusters in Mangochi district, Malawi to the community-led HIVST intervention in addition to the standard of care (SOC) or the SOC alone. The intervention involved mobilising community health groups to lead the design and implementation of 7-day HIVST campaigns, with cluster residents (≥15 years) eligible for HIVST. The primary outcome compared lifetime HIV testing among adolescents (15 to 19 years) between arms. Secondary outcomes compared: recent HIV testing (in the last 3 months) among older adults (≥40 years) and men; cumulative 6-month incidence of ART initiation per 100,000 population; knowledge of the preventive benefits of HIV treatment; and HIV testing stigma. Outcomes were measured through a post-intervention survey and at neighboring health facilities. Analysis used intention-to-treat for cluster-level outcomes.Community health groups delivered 24,316 oral fluid-based HIVST kits. The survey included 90.2% (3,960/4,388) of listed participants in the 15 community-led HIVST clusters and 89.2% (3,920/4,394) of listed participants in the 15 SOC clusters. Overall, the proportion of men was 39.0% (3,072/7,880). Most participants obtained primary-level education or below, were married, and reported a sexual partner. Lifetime HIV testing among adolescents was higher in the community-led HIVST arm (84.6%, 770/910) than the SOC arm (67.1%, 582/867; adjusted risk difference [RD] 15.2%, 95% CI 7.5% to 22.9%; p < 0.001), especially among 15 to 17 year olds and boys. Recent testing among older adults was also higher in the community-led HIVST arm (74.5%, 869/1,166) than the SOC arm (31.5%, 350/1,111; adjusted RD 42.1%, 95% CI 34.9% to 49.4%; p < 0.001). Similarly, the proportions of recently tested men were 74.6% (1,177/1,577) and 33.9% (507/1,495) in the community-led HIVST and SOC arms, respectively (adjusted RD 40.2%, 95% CI 32.9% to 47.4%; p < 0.001). Knowledge of HIV treatment benefits and HIV testing stigma showed no differences between arms. Cumulative incidence of ART initiation was respectively 305.3 and 226.1 per 100,000 population in the community-led HIVST and SOC arms (RD 72.3, 95% CI −36.2 to 180.8; p = 0.18). In post hoc analysis, ART initiations in the 3-month post-intervention period were higher in the community-led HIVST arm than the SOC arm (RD 97.7, 95% CI 33.4 to 162.1; p = 0.004). HIVST uptake was 74.7% (2,956/3,960), with few adverse events (0.6%, 18/2,955) and at US$5.70 per HIVST kit distributed. The main limitations include the use of self-reported HIV testing outcomes and lack of baseline measurement for the primary outcome.ConclusionsIn this study, we found that community-led HIVST was effective, safe, and affordable, with population impact and coverage rapidly realised at low cost. This approach could enable community HIV testing in high HIV prevalence settings and demonstrates potential for economies of scale and scope.Trial registrationClinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03541382","term_id":"NCT03541382"}}NCT03541382.

Pitchaya Indravudh and colleagues study community-led HIV self-testing in Malawi.     

Analysis and optimal control of an HIV model based on CD4 count

Journal of Mathematical Biology - A non-linear mechanistic model for the transmission dynamics of HIV/AIDS is developed and analyzed. The model classified the infected individuals based on their...     

Resting regulatory CD4 T cells: a site of HIV persistence in patients on long-term effective antiretroviral therapy

Background

In HIV-infected patients on long-term HAART, virus persistence in resting long-lived CD4 T cells is a major barrier to curing the infection. Cell quiescence, by favouring HIV latency, reduces the risk of recognition and cell destruction by cytotoxic lymphocytes. Several cell-activation-based approaches have been proposed to disrupt cell quiescence and then virus latency, but these approaches have not eradicated the virus. CD4⁺CD25⁺ regulatory T cells (Tregs) are a CD4⁺ T-cell subset with particular activation properties. We investigated the role of these cells in virus persistence in patients on long-term HAART.

Methodology/Principal Findings

We found evidence of infection of resting Tregs (HLADR⁻CD69⁻CD25^hiFoxP3⁺CD4⁺ T cells) purified from patients on prolonged HAART. HIV DNA harbouring cells appear more abundant in the Treg subset than in non-Tregs. The half-life of the Treg reservoir was estimated at 20 months. Since Tregs from patients on prolonged HAART showed hyporesponsiveness to cell activation and inhibition of HIV-specific cytotoxic T lymphocyte-related functions upon activation, therapeutics targeting cell quiescence to induce virus expression may not be appropriate for purging the Treg reservoir.

Conclusions

Our results identify Tregs as a particular compartment within the latent reservoir that may require a specific approach for its purging.     

HIV/AIDS患者机会性感染与CD4+ T淋巴细胞间的关联性

目的 研究人免疫缺陷病毒（HIV）感染者及艾滋病（AIDS）患者发生机会性感染的概率与自身CD4+ T淋巴细胞之间的关系,为HIV患者机会性感染的防治提供参考。方法 以2016年6月至2017年6月我院400例HIV患者为研究对象,回顾性分析不同CD4+T淋巴细胞计数HIV患者发生机会性感染的情况。结果 400例HIV患者发生机会性感染178例,总感染率为44.5%。CD4+T淋巴细胞计数≤50个/μL的患者机会性感染发生率（86.67%）最高,与其他各组比较差异有统计学意义（P<0.05）。随着CD4+ T淋巴细胞计数的减少,HIV患者机会性感染率升高。178例机会性感染者中,单一感染82例,2部位感染52例,3部位感染28例,4部位以上感染16例。感染病原体检测显示,细菌感染84例（47.19%）,结核杆菌感染36例（20.22%）,病毒感染30例（16.85%,包括巨细胞病毒感染18例、单纯疱疹病毒感染12例）,真菌感染77例（43.25%,包括假丝酵母感染35例,肺孢子菌感染20例,马尔尼菲青霉菌感染12例,新型隐球菌感染10例）,未明确病原体性质34例（19.10%）,复合感染多见。结论 CD4+ T淋巴细胞水平与HIV患者继发机会性感染的概率关系密切。HIV患者CD4+ T淋巴细胞水平的监测对其继发机会性感染的防控具有重要临床意义。     

接受高效抗逆转录病毒治疗的 HIV/AIDS患者血浆IL 35及其受体水平的动态变化

目的 检测接受高效抗逆转录病毒治疗(HAART)的人类免疫缺陷病毒(HIV)感染者/艾滋病(AIDS)患者血浆中白介素(IL) 35及其受体IL12rβ2、糖蛋白130(gp130)水平的动态变化及意义。 方法 选择我院2017年1月至2018年3月收治的41例HIV感染者/AIDS患者为研究对象,选择45例同期健康体检者为对照组。分别采集HIV/AIDS患者接受HAART药物0、1、6、12个月时的外周静脉血,检测血浆中的IL 35及其受体IL12rβ2、gp130水平,同时检测血浆HIV 1 RNA载量,分析IL 35与IL12rβ2、gp130、HIV 1 RNA以及IL12rβ2、gp130与HIV 1 RNA病毒载量的相关性。 结果 与对照组相比,接受HAART(0、1、6个月)时患者血浆中IL 35、IL12rβ2、gp130水平降低(均P结论 接受HAART的HIV/AIDS患者血浆IL 35及其受体IL12rβ2、gp130水平随着接受HAART时间的延长而逐渐升高,且与HIV 1 RNA载量关系密切。血浆IL 35及其受体IL12rβ2、gp130在抗HIV感染中可能发挥一定作用。     

HIV/AIDS患者CD4水平对甲状腺功能影响的比较研究

目的观察HIV/AIDS患者甲状腺功能的变化,了解HIV对内分泌的影响。方法检测168例HIV/AIDS患者TT4、TT3、FT4、FT3、TSH,并分析不同CD4水平对甲状腺功能影响。结果HIV/AIDS患者甲状腺功能可保持正常,但低CD4组的FT3、TSH水平低于高CD4组。结论HIV/AIDS患者甲状腺功能可保持正常,但HIV感染不同阶段会对内分泌系统有一定影响。HIV感染对甲状腺影响的具体机制尚不十分清楚,利用动物模型进行进一步研究非常必要。