Biphasic decay of intact SHIV genomes following initiation of antiretroviral therapy complicates analysis of interventions targeting the reservoir.

The latent reservoir for HIV-1 in resting CD4+ T cells persists despite antiretroviral therapy (ART) and precludes cure. Reservoir-targeting interventions are evaluated in ART-treated macaques infected with simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV). Efficacy is determined by reservoir measurements before and after the intervention. However, most proviruses persisting in the setting of ART are defective. In addition, intact HIV-1 and SIV genomes undergo complex, multiphasic decay observable when new infection events are blocked by ART. Intervention-induced elimination of latently infected cells must be distinguished from natural decay. Here, we address these issues for SHIV. We describe an intact proviral DNA assay that allows digital counting of SHIV genomes lacking common fatal defects. We show that intact SHIV genomes in circulating CD4+ T cells undergo biphasic decay during the first year of ART, with a rapid first phase (t1/2 = 30.1 d) and a slower second phase (t1/2 = 8.1 mo) that is still more rapid that the slow decay observed in people with HIV-1 on long-term ART (t1/2 = 3.7 y). In SHIV models, most interventions are tested during 2nd phase decay. Natural 2nd phase decay must be considered in evaluating interventions as most infected cells present at this time do not become part of the stable reservoir. In addition, for interventions tested during 2nd phase decay, a caveat is that the intervention may not be equally effective in people with HIV on long-term ART whose reservoirs are dominated by latently infected cells with a slower decay rate.

A quantitative approach for measuring the reservoir of latent HIV-1 proviruses.

A stable latent reservoir for HIV-1 in resting CD4+ T cells is the principal barrier to a cure1-3. Curative strategies that target the reservoir are being tested4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays for cells that release infectious virus after one round of T cell activation1. However, these quantitative outgrowth assays and newer assays for cells that produce viral RNA after activation6 may underestimate the reservoir size because one round of activation does not induce all proviruses7. Many studies rely on simple assays based on polymerase chain reaction to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority of proviruses are defective7-9. Here we describe a more accurate method of measuring the HIV-1 reservoir that separately quantifies intact and defective proviruses. We show that the dynamics of cells that carry intact and defective proviruses are different in vitro and in vivo. These findings have implications for targeting the intact proviruses that are a barrier to curing HIV infection.

Prostaglandin E-induced polycyclic cutaneous eruption with geometric features.

Prostaglandin E1 (PGE1) is a substance produced by the patent ductus arteriosus that keeps it open. PGE1 can be a lifesaving drug for infants born with ductus-dependent congenital heart disease (CHD) where there is a block of blood flow to the lungs or transposition of great arteries. We present a case of a 36-week, 2-day gestation neonate with CHD who developed bright erythematous annular and polycyclic patches on day 2 of PGE1 administration. When PGE1 dosing was decreased, the rash resolved on its own. Our case demonstrates that PGE1 treatment may not need to be interrupted.

Similar Frequency and Inducibility of Intact Human Immunodeficiency Virus-1 Proviruses in Blood and Lymph Nodes.

BACKGROUND: The human immunodeficiency virus (HIV)-1 latent reservoir (LR) in resting CD4+ T cells is a barrier to cure. LR measurements are commonly performed on blood samples and therefore may miss latently infected cells residing in tissues, including lymph nodes. METHODS: We determined the frequency of intact HIV-1 proviruses and proviral inducibility in matched peripheral blood (PB) and lymph node (LN) samples from 10 HIV-1-infected patients on antiretroviral therapy (ART) using the intact proviral DNA assay and a novel quantitative viral induction assay. Prominent viral sequences from induced viral RNA were characterized using a next-generation sequencing assay. RESULTS: The frequencies of CD4+ T cells with intact proviruses were not significantly different in PB versus LN (61/106 vs 104/106 CD4+ cells), and they were substantially lower than frequencies of CD4+ T cells with defective proviruses. The frequencies of CD4+ T cells induced to produce high levels of viral RNA were not significantly different in PB versus LN (4.3/106 vs 7.9/106), but they were 14-fold lower than the frequencies of cells with intact proviruses. Sequencing of HIV-1 RNA from induced proviruses revealed comparable sequences in paired PB and LN samples. CONCLUSIONS: These results further support the use of PB as an appropriate proxy for the HIV-1 LR in secondary lymphoid organs.

Racial differences in dermatologic conditions associated with HIV: A cross-sectional study of 4679 patients in an urban tertiary care center.

BACKGROUND: Because of reduced mortality, patients with HIV are living longer and presenting with chronic diseases. Little is known about racial differences in dermatologic conditions associated with HIV infection. OBJECTIVE: This study examines associated dermatologic conditions in a large population of patients with HIV at a tertiary care center with a diverse patient population. METHODS: Cross-sectional study of patients with HIV seen between July 14, 2013, and July 14, 2018, in a tertiary health care system. The burden of HIV-related dermatologic conditions was collected by using medical records. Patients with HIV were compared with control individuals of the same race, and significance was assessed using the chi-square test. A Bonferroni correction was performed to control for multiple hypothesis testing. RESULTS: The study population (N = 4679) was 64.7% male and 69% African American, with 88.7% of patients receiving antiretroviral therapy. African American patients with HIV had a greater risk of oral hairy leukoplakia (odds ratio [OR], 64.49), herpes zoster (OR, 9.27), prurigo nodularis (OR, 8.80), and squamous cell carcinoma (OR, 5.72). LIMITATIONS: Our data describe patients seen by 1 health care system. CONCLUSIONS: African American patients with HIV may be at increased risk for pruritic disorders compared with race-matched control individuals and white patients with HIV.

Antiretroviral therapy reveals triphasic decay of intact SIV genomes and persistence of ancestral variants.

The decay kinetics of HIV-1-infected cells are critical to understand virus persistence. We evaluated the frequency of simian immunodeficiency virus (SIV)-infected cells for 4 years of antiretroviral therapy (ART). The intact proviral DNA assay (IPDA) and an assay for hypermutated proviruses revealed short- and long-term infected cell dynamics in macaques starting ART ∼1 year after infection. Intact SIV genomes in circulating CD4+T cells showed triphasic decay with an initial phase slower than the decay of the plasma virus, a second phase faster than the second phase decay of intact HIV-1, and a stable third phase reached after 1.6-2.9 years. Hypermutated proviruses showed bi- or mono-phasic decay, reflecting different selective pressures. Viruses replicating at ART initiation had mutations conferring antibody escape. With time on ART, viruses with fewer mutations became more prominent, reflecting decay of variants replicating at ART initiation. Collectively, these findings confirm ART efficacy and indicate that cells enter the reservoir throughout untreated infection.

The Landscape of Persistent Viral Genomes in ART-Treated SIV, SHIV, and HIV-2 Infections.

Evaluation of HIV cure strategies is complicated by defective proviruses that persist in ART-treated patients but are irrelevant to cure. Non-human primates (NHP) are essential for testing cure strategies. However, the persisting proviral landscape in ART-treated NHPs is uncharacterized. Here, we describe viral genomes persisting in ART-treated, simian immunodeficiency virus (SIV)-infected NHPs, simian-human immunodeficiency virus (SHIV)-infected NHPs, and humans infected with HIV-2, an SIV-related virus. The landscapes of persisting SIV, SHIV, and HIV-2 genomes are also dominated by defective sequences. However, there was a significantly higher fraction of intact SIV proviral genomes compared to ART-treated HIV-1 or HIV-2 infected humans. Compared to humans with HIV-1, SIV-infected NHPs had more hypermutated genomes, a relative paucity of clonal SIV sequences, and a lower frequency of deleted genomes. Finally, we report an assay for measuring intact SIV genomes which may have value in cure research.

Solid Pseudopapillary Neoplasm of the Pancreas in a Young Pediatric Patient: A Case Report and Systematic Review of the Literature.

Solid pseudopapillary neoplasms (SPNs) are the most common pediatric pancreatic tumor; however, most data in children are extrapolated from adults. This study describes a young presentation of SPN in a 5-year-old girl and presents a comprehensive systematic review of the literature regarding SPNs in children. A systematic review was performed using PubMed and Embase for all articles in English using predetermined search terms, including "solid pseudopapillary neoplasm" and "pediatric" and historical terms for SPN. A total of 523 pediatric patients were identified in 135 articles. Eighty-three percent of patients were female, and median age was 13.6 years. Abdominal pain was the most frequent presenting symptom (78%), and median tumor size was 8.2 cm. The pancreatic head was involved in 46% of cases. Computed tomographic scan was the most common imaging modality (87%), and 61% were diagnosed by fine needle aspiration. Surgical resection was reported in 507 patients, with a complication rate of 21.1% reported in 393 patients. Only 3.8% received adjuvant therapy, and 6.7% had recurrent disease. Solid pseudopapillary neoplasms of the pancreas are rare tumors in childhood. Male sex and pancreatic head involvement are seen more often in children than in adults. Surgery remains the mainstay of treatment with excellent results.