HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study

Background: It is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART. Methods and findings Colorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection. Conclusions: We report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission

CD8 + T-cell responses in HIV controllers: potential implications for novel HIV remission strategies.

Purpose of reviewImmunological studies of spontaneous HIV and simian virus (SIV) controllers have identified virus-specific CD8 +  T cells as a key immune mechanism of viral control. The purpose of this review is to consider how knowledge about the mechanisms that are associated with CD8 +  T cell control of HIV/SIV in natural infection can be harnessed in HIV remission strategies.Recent findingsWe discuss characteristics of CD8 +  T-cell responses that may be critical for suppressing HIV replication in spontaneous controllers comprising HIV antigen recognition including specific human leukocyte antigen types, broadly cross-reactive T cell receptors and epitope targeting, enhanced expansion and antiviral functions, and localization of virus-specific T cells near sites of reservoir persistence. We also discuss the need to better understand the timing of CD8 +  T-cell responses associated with viral control of HIV/SIV during acute infection and after treatment interruption as well as the mechanisms by which HIV/SIV-specific CD8 +  T cells coordinate with other immune responses to achieve control.SummaryWe propose implications as to how this knowledge from natural infection can be applied in the design and evaluation of CD8 +  T-cell-based remission strategies and offer questions to consider as these strategies target distinct CD8 +  T-cell-dependent mechanisms of viral control

Generating and measuring effective vaccine-elicited HIV-specific CD8+ T cell responses

Purpose of reviewThere is growing consensus that eliciting CD8 + T cells in addition to antibodies may be required for an effective HIV vaccine for both prevention and cure. Here, we review key qualities of vaccine-elicited CD8 + T cells as well as major CD8 + T cell-based delivery platforms used in recent HIV vaccine clinical trials.Recent findingsMuch progress has been made in improving HIV immunogen design and delivery platforms to optimize CD8 + T cell responses. With regards to viral vectors, recent trials have tested newer chimp and human adenovirus vectors as well as a CMV vector. DNA vaccine immunogenicity has been increased by delivering the vaccines by electroporation and together with adjuvants as well as administering them as part of a heterologous regimen. In preclinical models, self-amplifying RNA vaccines can generate durable tissue-based CD8 + T cells. While it may be beneficial for HIV vaccines to recapitulate the functional and phenotypic features of HIV-specific CD8 + T cells isolated from elite controllers, most of these features are not routinely measured in HIV vaccine clinical trials.SummaryIdentifying a vaccine capable of generating durable T cell responses that target mutationally vulnerable epitopes and that can rapidly intercept infecting or rebounding virus remains a challenge for HIV. Comprehensive assessment of HIV vaccine-elicited CD8 + T cells, as well as comparisons between different vaccine platforms, will be critical to advance our understanding of how to design better CD8 + T cell-based vaccines for HIV

Clinical Utility of Universal Broad-Range Polymerase Chain Reaction Amplicon Sequencing for Pathogen Identification: A Retrospective Cohort Study.

We assessed the real-world utility of universal broad-range polymerase chain reaction sequencing for pathogen detection. Among 1062 clinical samples, 107/1062 (10.1%) had a clinically significant, positive result, with substantial variation by specimen type. Clinical management was changed in 44/1062 (4.1%). These data can help maximize utility of this emerging diagnostic

Think global, act local: chronic dysuria and sterile pyuria in an Eritrean-American woman

A 70-year-old female Eritrean immigrant living in the USA presented with classic findings of genitourinary (GU) tuberculosis (TB), including risk of tuberculosis exposure based on country of origin, chronic urinary tract symptoms and persistent sterile pyuria despite antibacterial therapy. Furthermore, this patient had the hallmark radiographical findings of ureteral stricture, a dilated pelvic calyceal system, hydroureteronephrosis and bladder wall thickening, as well as a bladder wall biopsy that revealed granulomatous disease. The patient was evaluated multiple times over the course of 3 years in outpatient and inpatient medical settings before a diagnosis was made and appropriate treatment initiated. As with many cases of GU TB, a protracted diagnosis allowed for advanced disease progression and significant morbidity from obstructive uropathy and chronic kidney disease

Transcriptional Repressor Blimp-1 Promotes CD8 + T Cell Terminal Differentiation and Represses the Acquisition of Central Memory T Cell Properties

During acute infections, a small population of effector CD8+ T cells evades terminal differentiation and survives as long-lived memory T cells. We demonstrate that the transcriptional repressor Blimp-1 enhanced the formation of terminally differentiate