Dietary algae and HIV/AIDS: proof of concept clinical data

Dietary algae have been reported to decrease HIV viral fusion/entry and replication and increase immune response, suggesting that regular consumption of algae by people in Japan, Korea, and Chad could be an important factor in their relatively low HIV/AIDS rates. Five antiretroviral-naïve people with HIV (three females, two males; five African Americans) living in Columbia SC participated in the phase I study of acute toxicity. Subjects were randomly assigned to 5 g day^-1 brown seaweed (Undaria pinnatifida), Spirulina (Arthrospira platensis), or a combination of both. Endpoints included HIV viral load, complete blood count (CBC), metabolic and lipid panel, and quality of life questionnaire data. When no short-term toxicities were observed, six additional subjects (four females, two males; five African Americans, one Latina) were recruited to further evaluate short- and long-term toxicities (phase II). No adverse effects were observed for the 11 subjects in the phase I trial, and quality of life indicators improved at 3 weeks. No significant changes were observed in CBC, metabolic or lipid panel analyses. CD4 cells (milliliters) and HIV-1 viral load remained stable over the first 3-month phase II study period. One subject continued in the study for 13 months and had clinically significant improvement in CD4 (>100 cells mL^?1) and decreased HIV viral load of 0.5 log₁₀. Our pilot data suggest that Undaria, Spirulina, and a combination of both were nontoxic and over time may improve clinical endpoints of HIV/AIDS.     

Elevated male European and female African contributions to the genomes of African American individuals

The differential relative contribution of males and females from Africa and Europe to individual African American genomes is relevant to mapping genes utilizing admixture analysis. The assessment of ancestral population contributions to the four types of genomic DNA (autosomes, X and Y chromosomes, and mitochondrial) with their differing modes of inheritance is most easily addressed in males. A thorough evaluation of 93 African American males for 2,018 autosomal single nucleotide polymorphic (SNP) markers, 121 X chromosome SNPs, 10 Y chromosome haplogroups specified by SNPs, and six haplogroup defining mtDNA SNPs is presented. A distinct lack of correlation observed between the X chromosome and the autosomal admixture fractions supports separate treatment of these chromosomes in admixture-based gene mapping applications. The European genetic contributions were highest (and African lowest) for the Y chromosome (28.46%), followed by the autosomes (19.99%), then the X chromosome (12.11%), and the mtDNA (8.51%). The relative order of admixture fractions in the genomic compartments validates previous studies that suggested sex-biased gene flow with elevated European male and African female contributions. There is a threefold higher European male contribution compared with European females (Y chromosome vs. mtDNA) to the genomes of African American individuals meaning that admixture-based gene discovery will have the most power for the autosomes and will be more limited for X chromosome analysis. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Reconstitution of EBV latent but not lytic antigen-specific CD4+ and CD8+ T cells after HIV treatment with highly active antiretroviral therapy

The incidence of (EBV-related) malignancies in HIV-infected subjects has declined since the introduction of highly active antiretroviral therapy (HAART). To investigate the effect of HAART on EBV infection, we performed a longitudinal analysis of the T cell response to both a latent and a lytic Ag and EBV viral load in 10 subjects from early in HIV infection up to 5 years after HAART. All individuals responded to HAART by a decline in HIV viral load, a restoration of total CD4+ T cell numbers, and a decline in T cell immune activation. Despite this, EBV load remained unaltered, even after 5 years of therapy, although a decline in both CD4+ and CD8+ T cells specific for the lytic EBV protein BZLF1 suggested a decreased EBV reactivation rate. In contrast, latent EBV Ag EBNA1-specific CD4+ and CD8+ T cell responses were restored after 5 years of treatment to levels comparable to healthy individuals. In two individuals who were treated by HAART late during HIV progression, a lymphoma developed shortly after initiation of HAART, despite restoration of EBV-specific CD4+ and CD8+ T cells. In conclusion, long-term HAART does not alter the EBV DNA load, but does lead to a restoration of EBNA1-specific T cell responses, which might allow better control of EBV-infected cells when applied early enough during HIV infection.     

Y chromosome haplogroups and prostate cancer in populations of European and Ashkenazi Jewish ancestry

Genetic variation on the Y chromosome has not been convincingly implicated in prostate cancer risk. To comprehensively analyze the role of inherited Y chromosome variation in prostate cancer risk in individuals of European ancestry, we genotyped 34 binary Y chromosome markers in 3,995 prostate cancer cases and 3,815 control subjects drawn from four studies. In this set, we identified nominally significant association between a rare haplogroup, E1b1b1c, and prostate cancer in stage I (P = 0.012, OR = 0.51; 95% confidence interval 0.30-0.87). Population substructure of E1b1b1c carriers suggested Ashkenazi Jewish ancestry, prompting a replication phase in individuals of both European and Ashkenazi Jewish ancestry. The association was not significant for prostate cancer overall in studies of either Ashkenazi Jewish (1,686 cases and 1,597 control subjects) or European (686 cases and 734 control subjects) ancestry (P(meta) = 0.078), but a meta-analysis of stage I and II studies revealed a nominally significant association with prostate cancer risk (P(meta) = 0.010, OR = 0.77; 95% confidence interval 0.62-0.94). Comparing haplogroup frequencies between studies, we noted strong similarities between those conducted in the US and France, in which the majority of men carried R1 haplogroups, resembling Northwestern European populations. On the other hand, Finns had a remarkably different haplogroup distribution with a preponderance of N1c and I1 haplogroups. In summary, our results suggest that inherited Y chromosome variation plays a limited role in prostate cancer etiology in European populations but warrant follow-up in additional large and well characterized studies of multiple ethnic backgrounds.     

Genetic Variants in Nuclear-Encoded Mitochondrial Genes Influence AIDS Progression

Background

The human mitochondrial genome includes only 13 coding genes while nuclear-encoded genes account for 99% of proteins responsible for mitochondrial morphology, redox regulation, and energetics. Mitochondrial pathogenesis occurs in HIV patients and genetically, mitochondrial DNA haplogroups with presumed functional differences have been associated with differential AIDS progression.

Methodology/Principal Findings

Here we explore whether single nucleotide polymorphisms (SNPs) within 904 of the estimated 1,500 genes that specify nuclear-encoded mitochondrial proteins (NEMPs) influence AIDS progression among HIV-1 infected patients. We examined NEMPs for association with the rate of AIDS progression using genotypes generated by an Affymetrix 6.0 genotyping array of 1,455 European American patients from five US AIDS cohorts. Successfully genotyped SNPs gave 50% or better haplotype coverage for 679 of known NEMP genes. With a Bonferroni adjustment for the number of genes and tests examined, multiple SNPs within two NEMP genes showed significant association with AIDS progression: acyl-CoA synthetase medium-chain family member 4 (ACSM4) on chromosome 12 and peroxisomal D3,D2-enoyl-CoA isomerase (PECI) on chromosome 6.

Conclusions

Our previous studies on mitochondrial DNA showed that European haplogroups with presumed functional differences were associated with AIDS progression and HAART mediated adverse events. The modest influences of nuclear-encoded mitochondrial genes found in the current study add support to the idea that mitochondrial function plays a role in AIDS pathogenesis.     

Greater adherence to highly active antiretroviral therapy (HAART) between pregnant versus non-pregnant women living with HIV.

One of the most remarkable advances in the control of the HIV/AIDS pandemic has been the introduction of highly active antiretroviral therapy (HAART). The use of HAART has been associated to reductions in AIDS-related mortality in most countries where HAART is available. Unfortunately, the adherence required to keep good control of viral replication is higher than what is required in other medical conditions. Several studies have shown a relationship between adherence and viral suppression ranging between 90-95% required for complete suppression. Multiple factors have been related to adherence among which are: gender, racial/ethnic distribution, age, personality traits, education, alcohol use and others. For women living with HIV there might be additional difficulties to handle in order to be adherent (i.e. multiple family responsibilities). A group of 165 women living with HIV attending a multidisciplinary clinic were interviewed with a 3-day adherence questionnaire. Correlation with clinical information was obtained from the Clinic Data Base. A total of 37 pregnant and 128 non-pregnant women were included in this analysis, 96% of which were on HAART. Complete adherence (100%) was reported by 91% of the pregnant and 70% of the non-pregnant women. (Fisher's exact test 0.009). The majority, 99% knew the names of their medications. There were no differences among groups in scholarity, history or actual cigarette smoking, history or actual drug use, CD4 lymphocyte counts (median or proportion below 350 cells/mm3), mean HIV RNA viral load or the proportion of patients with HIV RNA < 1,000 copies/ml. The transmission rate for the sample of pregnant women was zero. The reported adherence rates to HAART for women living with HIV were highest among the pregnant women. This difference was statistically significant (Chi Sq 0.05). The great majority (93%) reported knowing the names of the medications. In spite of reported barriers to adherence, pregnant women attending a multidisciplinary clinic for HIV care and research, reported good rates of adherence to HAART. This is also reflected in the good perinatal outcomes. Non-pregnant women with lower adherence rates might need additional interventions to improve adherence.     

Current progress and challenges in HIV gene therapy

HIV-1 causes AIDS, a syndrome that affects millions of people globally. Existing HAART is efficient in slowing down disease progression but cannot eradicate the virus. Furthermore the severity of the side effects and the emergence of drug-resistant mutants call for better therapy. Gene therapy serves as an attractive alternative as it reconstitutes the immune system with HIV-resistant cells and could thereby provide a potential cure. The feasibility of this approach was first demonstrated with the 'Berlin patient', who was functionally cured from HIV/AIDS with undetectable HIV-1 viral load after transplantation of bone marrow harboring a naturally occurring CCR5 mutation that blocks viral entry. Here, we give an overview of the current status of HIV gene therapy and remaining challenges and obstacles.     

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.     

Exploring the legacy of African and Indigenous Caribbean admixture in Puerto Rico

Objectives

From an anthropological genetic perspective, little is known about the ethnogenesis of African descendants in Puerto Rico. Furthermore, historical interactions between Indigenous Caribbean and African descendant peoples that may be reflected in the ancestry of contemporary populations are understudied. Given this dearth of genetic research and the precedence for Afro-Indigenous interactions documented by historical, archeological, and other lines of evidence, we sought to assess the biogeographic origins of African descendant Puerto Ricans and to query the potential for Indigenous ancestry within this community.

Materials and Methods

Saliva samples were collected from 58 self-identified African descendant Puerto Ricans residing in Puerto Rico. We sequenced whole mitochondrial genomes and genotyped Y chromosome haplogroups for each male individual (n = 25). Summary statistics, comparative analyses, and network analysis were used to assess diversity and variation in haplogroup distribution between the sample and comparative populations.

Results

As indicated by mitochondrial haplogroups, 66% had African, 5% had European, and 29% had Indigenous American matrilines. Along the Y chromosome, 52% had African, 28% had Western European, 16% had Eurasian, and, notably, 4% had Indigenous American patrilines. Both mitochondrial and Y chromosome haplogroup frequencies were significantly different from several comparative populations.

Discussion

Biogeographic origins are consistent with historical accounts of African, Indigenous American, and European ancestry. However, this first report of Indigenous American paternal ancestry in Puerto Rico suggests distinctive features within African descendant communities on the island. Future studies expanding sampling and incorporating higher resolution genetic markers are necessary to more fully understand African descendant history in Puerto Rico.     

A review of vaccines for HIV prevention

HIV/AIDS has become the most devastating pandemic in recorded history. It has killed 40 million people in the last 20 years and the World Health Organisation estimated that at least 14,000 new infections occurred daily in 2001. There will be up to 100 million new infections in the next 10 years (for current updates, visit http://www.unaids.org/epidemic_update/). Most HIV infections occur in the developing world, and the adverse social and economic impact of the HIV/AIDS pandemic, particularly in the developing world, is unprecedented. Highly active antiretroviral therapy (HAART) has had significant effects on HIV/AIDS in the developed world. The drugs have acted to prolong survival, reduce the viral load, and to alleviate suffering. However, the incidence of side effects and resistance is high and the drugs are unaffordable and unavailable in the developing world. HAART regimens are difficult to comply with. Public health efforts to modify the behaviour, attitude and culture that accelerate the spread of HIV/AIDS have had only modest success. There is urgent need for a prophylactic and/or therapeutic HIV vaccine. This is a review of the obstacles and current trends in HIV vaccine development.     

Role of APOBEC3F Gene Variation in HIV-1 Disease Progression and Pneumocystis Pneumonia

Human APOBEC3 cytidine deaminases are intrinsic resistance factors to HIV-1. However, HIV-1 encodes a viral infectivity factor (Vif) that degrades APOBEC3 proteins. In vitro APOBEC3F (A3F) anti-HIV-1 activity is weaker than A3G but is partially resistant to Vif degradation unlike A3G. It is unknown whether A3F protein affects HIV-1 disease in vivo. To assess the effect of A3F gene on host susceptibility to HIV- acquisition and disease progression, we performed a genetic association study in six well-characterized HIV-1 natural cohorts. A common six-Single Nucleotide Polymorphism (SNP) haplotype of A3F tagged by a codon-changing variant (p. I231V, with allele (V) frequency of 48% in European Americans) was associated with significantly lower set-point viral load and slower rate of progression to AIDS (Relative Hazards (RH) = 0.71, 95% CI: 0.56, 0.91) and delayed development of pneumocystis pneumonia (PCP) (RH = 0.53, 95% CI: 0.37–0.76). A validation study in the International Collaboration for the Genomics of HIV (ICGH) showed a consistent association with lower set-point viral load. An in vitro assay revealed that the A3F I231V variant may influence Vif mediated A3F degradation. Our results provide genetic epidemiological evidence that A3F modulates HIV-1/AIDS disease progression.     

Distribution and Determinants of Cytomegalovirus Induced End Organ Disease/s among People Living with HIV/AIDS in a Poor Resource Setting: Observation from India

BackgroundIn India, despite well-established anti-retroviral treatment programs, Cytomegalovirus (CMV) infection-related end-organ diseases (EODs) still remain a major concern resulting in exacerbation of morbidity and mortality among HIV/AIDS patients. A prospective study was designed to understand the distribution and prognosis of CMV associated EODs and to determine a standardized cut-off value for serum CMV viral load associated with the development of EODs amongst HIV/AIDS subjects.MethodsIn a cohort of 400 late-diagnosed HAART naïve HIV/AIDS subjects attending anti-retroviral centers of Kolkata during 2008–2014, the median duration of follow-up was 560 days, and at least 3 visits subsequent to the baseline were mandatory for eligibility. HIV-1 and CMV viral load were estimated by performing Real-Time Polymerase Chain Reactions (PCR).ResultsAmong subjects, 40.5% (162/400) had CMV EODs which were more common at lower CD4 counts. Poor prognosis and higher death rate were associated with a low CD4 count and increased HIV-1 and CMV viral loads. Subjects having higher CD4 count responded better to therapy [for CD4 = 60–100: Risk Ratio:RR = 1.48 (95% Confidence Interval: 95%CI = 1.18–1.82) and for CD4 = 30–59: RR = 1.64 (95%CI = 1.18–2.27)]. The cut off value of the serum CMV viral load (expressed as log10DNA/ml serum) associated with the development of EODs and disseminated CMV EODs was determined as 5.4 (p<0.0001) and 6.4 (p<0.0001) respectively. These cut offs were found to have satisfactorily high sensitivity, specificity, positive and negative predictive values.ConclusionPrognosis of CMV EOD was poor as indicated by higher death rates among subjects with lower CD4 count, and specific cut-off values were found to have useful potential for identification and treatment of CMV infected HIV/AIDS patients in due time to avoid CMV EODs among HIV/AIDS subjects. Targeted intervention programs seemed to be required urgently to make these cut-offs operational in order to minimize the burden of CMV EOD in this vulnerable population.     

Regulatory polymorphisms in the cyclophilin A gene, PPIA, accelerate progression to AIDS

Human cyclophilin A, or CypA, encoded by the gene peptidyl prolyl isomerase A (PPIA), is incorporated into the HIV type 1 (HIV-1) virion and promotes HIV-1 infectivity by facilitating virus uncoating. We examined the effect of single nucleotide polymorphisms (SNPs) and haplotypes within the PPIA gene on HIV-1 infection and disease progression in five HIV-1 longitudinal history cohorts. Kaplan-Meier survival statistics and Cox proportional hazards model were used to assess time to AIDS outcomes. Among eight SNPs tested, two promoter SNPs (SNP3 and SNP4) in perfect linkage disequilibrium were associated with more rapid CD4(+) T-cell loss (relative hazard = 3.7, p = 0.003) in African Americans. Among European Americans, these alleles were also associated with a significant trend to more rapid progression to AIDS in a multi-point categorical analysis (p = 0.005). Both SNPs showed differential nuclear protein-binding efficiencies in a gel shift assay. In addition, one SNP (SNP5) located in the 5' UTR previously shown to be associated with higher ex vivo HIV-1 replication was found to be more frequent in HIV-1-positive individuals than in those highly exposed uninfected individuals. These results implicate regulatory PPIA polymorphisms as a component of genetic susceptibility to HIV-1 infection or disease progression, affirming the important role of PPIA in HIV-1 pathogenesis.     

Heterogeneity of the Y chromosome in Afro-Brazilian populations

Sixteen biallelic markers (SRY10831a, SRY10831b, SRY4064, SRY2627, 92R7, P2, P3, M34, M9, M3, M2, YAP, M60, M89, M213, M216) located in the nonrecombinant region of the Y chromosome were analyzed in 209 individuals belonging to six Brazilian populations: four Afro-Brazilian populations, one population of white European descendants, and one population of Japanese descendants. The results showed that most of the Y chromosomes of the Afro-Brazilians were from sub-Saharan Africa and that the proportion of Y chromosomes of European origin was greater than that of Y chromosomes of Amerindian origin. No typical African or Amerindian haplogroup was detected among Japanese individuals, and only one white individual showed a typical African haplogroup. Haplogroup P-92R7, which is highly frequent in the Portuguese and Italian populations, was the most frequent among whites (54%), and haplogroup K-M9, which shows wide geographic distribution and is absent in Africa, was the most frequent among Japanese individuals (65.6%). The two semi-isolated Afro-Brazilian populations showed the highest and the lowest genetic diversity, respectively. These differences probably reflect the effect of greater or smaller gene flow between a small isolated group and other populations. These findings show that the process of admixture does not occur homogeneously, with a tendency toward preferential marriages within the ethnic group and a clear direction in unions between European men and Amerindian or African women in the past. The results agree with historical and social data about the formation of the Brazilian population and reveal some of the factors that contribute to its heterogeneity.     

Meaning of DNA detection during the follow-up of HIV-1 infected patients: a brief review

A growing body of evidence indicates that proviral DNA load quantitation is an important parameter in establishing the dynamics of HIV infection. Proviral DNA load can be determined during the follow-up of infected individuals to evaluate reservoir status in addition to viral replication. Hence, the study of viral reservoirs, represented by HIV-1 latently infected cells, including resting memory CD4+ T cells, monocytes and macrophages, by which HIV-1 can be reactivated, opens new perspectives in the assessment and the comprehension of HIV-1 infection. However, the identification of viral reservoirs, that can store both wild and drug resistance viruses, is one of the most important steps in developing treatment strategies because it is now clear that viral reservoirs not only prevent sterilizing immunity but also represent a major obstacle to curing the infection with the potent antiretroviral drugs currently in use. Even if only careful evaluation of virological and immunological markers is necessary to fully characterize the course of HIV-1 infection and to provide a more complete laboratory-based assessment of disease progression, the availability of a new standardized assay such as DNA proviral load will be important to assess the true extent of virological suppression in treated patients and to verify the efficacy of new immune-based therapies aimed at purging HIV-1 DNA reservoirs. Several studies demonstrate, in fact, that HIV-1 cellular DNA load may be an indicator of spread of infection whereas the plasma RNA load is indicates active infection. This article will review the importance of monitoring HIV-1 proviral load DNA during the follow-up of HIV-1 infected subjects, suggesting that additional information complementing HIV RNA load could provide crucial information to monitor viral replication and the effectiveness of HAART therapy.     

Boundaries and clines in the West Eurasian Y-chromosome landscape: insights from the European part of Russia

Previous studies of Y chromosome variation have revealed that western Europe, the Volga-Ural region, and the Caucasus differ dramatically with respect to Y-SNP haplogroup composition. The European part of Russia is situated in between these three regions; to determine if these differences reflect clines or boundaries in the Y-chromosome landscape, we analyzed 12 Y-SNPs in 545 males from 12 populations from the European part of Russia. The majority of Russian Y chromosomes (from 74% to 94%) belong to three Y chromosomal lineages [I-M170, R1a1-M17, and N3-TAT] that are also frequent in the rest of east Europe, north Europe, and/or in the Volga-Ural region. We find significant but low correlations between haplogroup frequencies and the geographic location of populations, suggesting gradual change in the Y chromosome gene pool across western Eurasia. However, we also find some significant boundaries between populations, suggesting that both isolation and migration have influenced the Y chromosome landscape.     

Evaluation of Group Genetic Ancestry of Populations from Philadelphia and Dakar in the Context of Sex-Biased Admixture in the Americas

Background

Population history can be reflected in group genetic ancestry, where genomic variation captured by the mitochondrial DNA (mtDNA) and non-recombining portion of the Y chromosome (NRY) can separate female- and male-specific admixture processes. Genetic ancestry may influence genetic association studies due to differences in individual admixture within recently admixed populations like African Americans.

Principal Findings

We evaluated the genetic ancestry of Senegalese as well as European Americans and African Americans from Philadelphia. Senegalese mtDNA consisted of ∼12% U haplotypes (U6 and U5b1b haplotypes, common in North Africa) while the NRY haplotypes belonged solely to haplogroup E. In Philadelphia, we observed varying degrees of admixture. While African Americans have 9–10% mtDNAs and ∼31% NRYs of European origin, these results are not mirrored in the mtDNA/NRY pools of European Americans: they have less than 7% mtDNAs and less than 2% NRYs from non-European sources. Additionally, there is <2% Native American contribution to Philadelphian African American ancestry and the admixture from combined mtDNA/NRY estimates is consistent with the admixture derived from autosomal genetic data. To further dissect these estimates, we have analyzed our samples in the context of different demographic groups in the Americas.

Conclusions

We found that sex-biased admixture in African-derived populations is present throughout the Americas, with continual influence of European males, while Native American females contribute mainly to populations of the Caribbean and South America. The high non-European female contribution to the pool of European-derived populations is consistently characteristic of Iberian colonization. These data suggest that genomic data correlate well with historical records of colonization in the Americas.     

The amplitudes of viral blips in HIV-1 infected patients treated with antiretroviral therapy are power-law distributed

We previously reported that in patients treated with highly active antiretroviral therapy (HAART) who achieve viral load (VL) suppression, low fluctuations of viral load over the threshold of detection (viral blips) more than 4 weeks apart occur at random, with a frequency that does not change with longer times of observation. The etiology of viral blips is currently unknown, but viral blip frequency inversely correlates with the decay of the latent reservoir, whose stability has been proposed as the major hurdle to HIV eradication. We show here that the distribution of viral blip amplitudes observed in a group of 272 patients successfully treated with highly active antiretroviral therapy appears to be power-law distributed. Such a distribution can be theoretically generated by randomly sampling the arrival of asynchronous and overlapping elementary pulses of viremia, with asymptotic exponential decay of kinetics, thus suggesting that the low fluctuations of viremia observed in patients during HAART treatment is, in part, a discrete phenomenon consistent with random activation of latently infected cells or release of virus and infected cells into the blood compartment from unknown sites of active viral replication.