The source and dynamics of persistent HIV-1 during long-term combinational antiretroviral therapy (cART) are critical to understanding the barriers to curing HIV-1 infection. To address this issue, ...we isolated and genetically characterized HIV-1 DNA from naïve and memory T cells from peripheral blood and gut-associated lymphoid tissue (GALT) from eight patients after 4–12 y of suppressive cART. Our detailed analysis of these eight patients indicates that persistent HIV-1 in peripheral blood and GALT is found primarily in memory CD4 ⁺ T cells CD45RO ⁺/CD27(⁺/⁻). The HIV-1 infection frequency of CD4 ⁺ T cells from peripheral blood and GALT was higher in patients who initiated treatment during chronic compared with acute/early infection, indicating that early initiation of therapy results in lower HIV-1 reservoir size in blood and gut. Phylogenetic analysis revealed an HIV-1 genetic change between RNA sequences isolated before initiation of cART and intracellular HIV-1 sequences from the T-cell subsets after 4–12 y of suppressive cART in four of the eight patients. However, evolutionary rate analyses estimated no greater than three nucleotide substitutions per gene region analyzed during all of the 4–12 y of suppressive therapy. We also identified a clearly replication-incompetent viral sequence in multiple memory T cells in one patient, strongly supporting asynchronous cell replication of a cell containing integrated HIV-1 DNA as the source. This study indicates that persistence of a remarkably stable population of infected memory cells will be the primary barrier to a cure, and, with little evidence of viral replication, this population could be maintained by homeostatic cell proliferation or other processes.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Racial and ethnic minority, sexual and gender minority, and low-income people have historically experienced poorer health outcomes and poorer social conditions that lead to poorer health outcomes ...(social determinants of health) than nonminority people in the United States. To eliminate these health disparities, intentional and targeted interventions that address the needs and preferences of diverse populations are needed. To address disparities, the California HIV/AIDS Research Program focused their funding resources tightly on communities facing elevated HIV incidence or prevalence. This special issue describes interventions that aimed to increase linkage to and engagement in HIV-specific prevention or medical care, each uniquely tailored to the needs of an identified California population with disparate HIV-related health outcomes and each for implementation at a specific stage of the HIV prevention and care continuum.
We assessed changes in sexual behavior among men who have sex with men (MSM), before and for several years after HIV diagnosis, accounting for adoption of a variety of seroadaptive practices.
We ...collected self-reported sexual behavior data every 3 months from HIV-positive MSM at various stages of HIV infection. To establish population level trends in sexual behavior, we used negative binomial regression to model the relationship between time since diagnosis and several sexual behavior variables: numbers of (a) total partners, (b) potentially discordant partners (PDP; i.e., HIV-negative or unknown-status partners), (c) PDPs with whom unprotected anal intercourse (UAI) occurred, and (d) PDPs with whom unprotected insertive anal intercourse (uIAI) occurred.
A total of 237 HIV-positive MSM contributed 502 interviews. UAI with PDPs occurred with a mean of 4.2 partners in the 3 months before diagnosis. This declined to 0.9 partners/3 months at 12 months after diagnosis, and subsequently rose to 1.7 partners/3 months at 48 months, before falling again to 1.0 partners/3 months at 60 months. The number of PDPs with whom uIAI occurred dropped from 2.4 in the pre-diagnosis period to 0.3 partners/3 months (an 87.5% reduction) by 12 months after enrollment, and continued to decline over time.
Within months after being diagnosed with HIV, MSM adopted seroadaptive practices, especially seropositioning, where the HIV-positive partner was not in the insertive position during UAI, resulting in a sustained decline in the sexual activity associated with the highest risk of HIV transmission.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Transmitted HIV-1 drug resistance (TDR) is an ongoing public health problem, representing 10-20% of new HIV infections in many geographic areas. TDR usually arises from two main sources: individuals ...on antiretroviral therapy (ART) who are failing to achieve virologic suppression, and individuals who acquired TDR and transmit it while still ART-naïve. TDR rates can be impacted when novel antiretroviral medications are introduced that allow for greater virologic suppression of source patients. Although several new HIV medications were introduced starting in late 2007, including raltegravir, maraviroc, and etravirine, it is not known whether the prevalence of TDR was subsequently affected in 2008-2009.
We performed population sequence genotyping on individuals who were diagnosed with acute or early HIV (<6 months duration) and who enrolled in the Options Project, a prospective cohort, between 2002 and 2009. We used logistic regression to compare the odds of acquiring drug-resistant HIV before versus after the arrival of new ART (2005-2007 vs. 2008-2009). From 2003-2007, TDR rose from 7% to 24%. Prevalence of TDR was then 15% in 2008 and in 2009. While the odds of acquiring TDR were lower in 2008-2009 compared to 2005-2007, this was not statistically significant (odds ratio 0.65, 95% CI 0.31-1.38; p = 0.27).
Our study suggests that transmitted drug resistance rose from 2003-2007, but this upward trend did not continue in 2008 and 2009. Nevertheless, the TDR prevalence in 2008-2009 remained substantial, emphasizing that improved management strategies for drug-resistant HIV are needed if TDR is to be further reduced. Continued surveillance for TDR will be important in understanding the full impact of new antiretroviral medications.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
CD8+ T cells are important for HIV-1 virus control, but are also a major contributing factor that drives HIV-1 virus sequence evolution. Although HIV-1 cytotoxic T cell (CTL) escape mutations are a ...common aspect during HIV-1 infection, less is known about the importance of T cell pressure in reversing HIV-1 virus back to a consensus sequences. In this study we aimed to assess the frequency with which reversion of transmitted mutations in T cell epitopes were associated with T cell responses to the mutation. This study included 14 HIV-1 transmission pairs consisting of a 'source' (virus-donor) and a 'recipient' (newly infected individual). Non-consensus B sequence amino acids (mutations) in T cell epitopes in HIV-1 gag regions p17, p24, p2 and p7 were identified in each pair and transmission of mutations to the recipient was verified with population viral sequencing. Longitudinal analyses of the recipient's viral sequence were used to identify whether reversion of mutations back to the consensus B sequence occurred. Autologous 12-mer peptides overlapping by 11 were synthesized, representing the sequence region surrounding each reversion and longitudinal analysis of T cell responses to source-derived mutated and reverted epitopes were assessed. We demonstrated that mutations in the source were frequently transmitted to the new host and on an average 17 percent of mutated epitopes reverted to consensus sequence in the recipient. T cell responses to these mutated epitopes were detected in 7 of the 14 recipients in whom reversion occurred. Overall, these findings indicate that transmitted non-consensus B epitopes are frequently immunogenic in HLA-mismatched recipients and new T cell pressures to T cell escape mutations following transmission play a significant role in maintaining consensus HIV-1 sequences.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. The stability of the human immunodeficiency virus type 1 (HIV-1) reservoir and the contribution of cellular proliferation to the maintenance of the reservoir during treatment are ...uncertain. Therefore, we conducted a longitudinal analysis of HIV-1 in T-cell subsets in different tissue compartments from subjects receiving effective antiretroviral therapy (ART). Methods. Using single-proviral sequencing, we isolated intracellular HIV-1 genomes derived from defined subsets of CD4⁺ T cells from peripheral blood, gut-associated lymphoid tissue and lymph node tissue specimens from 8 subjects with virologie suppression during long-term ART at 2 time points (time points 1 and 2) separated by 7-9 months. Results. DNA integrant frequencies were stable over time (<4-fold difference) and highest in memory T cells. Phylogenetic analyses showed that subjects treated during chronic infection contained viral populations with up to 73% identical sequence expansions, only 3 of which were observed in specimens obtained before therapy. At time points 1 and 2, such clonally expanded populations were found predominantly in effector memory T cells from peripheral blood and lymph node tissue specimens. Conclusions. Memory T cells maintained a relatively constant HIV-1 DNA integrant pool that was genetically stable during long-term effective ART. These integrants appear to be maintained by cellular proliferation and longevity of infected cells, rather than by ongoing viral replication.
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Loss of genetic variation is an increasing problem in many natural populations as a result of population fragmentation, inbreeding, and genetic drift, which may lead to inbreeding depression and ...subsequent “extinction vortices”. In such cases, outbreeding offers a potential population saviour from extinction. Here we compare offspring viability between an experimentally founded outbred island population of sand lizards Lacerta agilis, and an inbred mainland source population on the Swedish West coast. We have studied the mainland population for over a decade during which >4000 offspring from >500 parents were monitored. We conducted an outbreeding experiment in which lizards from the mainland population with relatively low genetic variation were crossbred with lizards from distant populations that lack gene flow. The resulting 454 offspring were introduced to an otherwise uninhabited island with ideal sand lizard habitat. A survey of the island two decades later showed that offspring produced by females from the experimentally founded population had 13% higher hatching success (99.3% versus 86.4%) and elimination of the malformations occurring in 21% of clutches in the mainland source population. These results co-occur with higher genetic diversity. We conclude that outbreeding improved offspring viability in our island population ca 5–6 generations after the founding event, that is, with sustained viability effects at a time when heterotic effects are expected to have subsided.
•Fragmented populations are often inbred with low genetic diversity.•Outbreeding with other populations can rescue genetic diversity.•Sand lizard populations of Southern Sweden are threatened by inbreeding.•Outbreeding improved offspring viability of sand lizards for six generations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background. We address the key emerging question of whether Lin - /CD34 + hematopoietic precursor cells (HPCs) represent an important latent reservoir of human immunodeficiency virus type 1 (HIV-1) ...during long-term suppressive therapy. Methods. To estimate the frequency of HIV-1 infection in bone marrow, we sorted Lin - /CD34 + HPCs and 3 other cell types (Lin - /CD34 - , Lin - /CD4 + , and Lin + /CD4 + ) from 8 patients who had undetectable viral loads for 3—12 years. Using a single-proviral sequencing method, we extracted, amplified, and sequenced multiple single HIV-1 DNA molecules from these cells and memory CD4 + T cells from contemporaneous peripheral blood samples. Results. We analyzed 100 000—870 000 bone marrow Lin - /CD34 + HPCs from the 8 patients and found no HIV-1 DNA. We did isolate HIV-1 DNA from their bone marrow Lin + /CD4 + cells that was genetically similar to HIV-1 DNA from lymphoid cells located in the peripheral blood, indicating an exchange of infected cells between these compartments. Conclusions. The absence of infected HPCs provides strong evidence that the HIV-1 infection frequency of Lin - /CD34 + HPCs from bone marrow, if it occurred, was <.003% (highest upper 95% confidence interval) in all 8 patients. These results strongly suggest that Lin - /CD34 + HPCs in bone marrow are not a source of persistent HIV-1 in patients on long-term suppressive therapy.
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This Special Issue of AIDS Research and Human Retroviruses features results from the HIV Cure Initiative, funded by the California HIV/AIDS Research Program (CHRP). As a publicly funded grant maker, ...CHRP has served for more than three decades as a unique resource for innovative researchers in California, whose work seeks to address all aspects of the HIV epidemic and the communities affected by it. Early initiatives at CHRP pioneered what would become enduring cornerstones of HIV science: isolation of the virus; efficacy and toxicities of the first HIV treatments; the emergence of drug resistance; the first biospecimen banks for HIV-related research; the first community-based laboratory service for HIV diagnostic serology; and the first longitudinal case-control study of progression from HIV to AIDS-The San Francisco General Hospital Cohort. More recently, CHRP-funded conceptual studies of zinc-finger nuclease-mediated disruption of CCR5 genomic sequences and the safety of solid organ transplantation for HIV-positive patients have progressed from brilliant ideas to clinical realities, and CHRP is currently funding the first multisite trial of HIV preexposure prophylaxis for transgender persons in the United States. The present article outlines the founding of CHRP, our current grantmaking process, and our impact on HIV research over time. In 2013, CHRP launched a new initiative aimed at moving the then nascent frontier of HIV cure science forward: the CHRP HIV Cure Initiative provided over $1.4 million to multiple basic biomedical research projects, and selected results are presented in this Special Issue.
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