Distribution of Human Immunodeficiency Virus (HIV) Ribonucleic Acid in Cerebrospinal Fluid and Blood Is Linked to CD4/CD8 Ratio During Acute HIV

Chan, Phillip; Patel, Payal; Hellmuth, Joanna; Colby, Donn; Kroon, Eugène; Sacdalan, Carlo; Pinyakorn, Suteeraporn; Jagodzinski, Linda L.; Krebs, Shelly J.; Ananworanich, Jintanat; Valcour, Victor; Spudich, Serena; Team, Search Study

doi:10.1093/infdis/jiy260

Cited by 18 publications

(16 citation statements)

References 40 publications

(47 reference statements)

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“…These findings are consistent with recent epidemiological reports about syphilis in other societies [2,13,25]. We previously reported that untreated syphilis had no measurable effect on CSF HIV-1 RNA levels in a subset of cohort participants who underwent optional LP for research purposes during untreated AHI [11]. The current analysis focused primarily on the effects of clinical parameters by syphilis, which compared individuals with any syphilis and untreated syphilis with those without any prior syphilis at the time of AHI.…”

Section: Discussionsupporting

confidence: 89%

“…Participants included all 595 individuals enrolled into the SEARCH010/RV254 cohort (NCT00796146) between April 2009 and March 2019. The methodology and primary goals of the cohort study have been described elsewhere [11]. Briefly, these individuals enrolled in voluntary HIV counselling and testing services offered in Bangkok, Thailand, which systematically screened for AHI.…”

Section: Study Design and Participantsmentioning

confidence: 99%

“…Moreover, PWLH experience a higher rate of syphilis treatment failure compared with individuals without HIV-1 [7][8][9]. While both pathogens invade the central nervous system (CNS) within days after initial infection [10,11], neurosyphilis, defined as at least one of the two criteria including reactive cerebrospinal fluid (CSF)-Venereal Disease Research Laboratory (VDRL) test and CSF pleocytosis, may be more common among PLWH [12,13]. An association between prior syphilis and poorer cognitive performance in chronic HIV-1 infection in the absence of overt neurosyphilis has been inconsistently reported in different studies [14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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Clinical and laboratory impact of concomitant syphilis infection during acute HIV

et al. 2021

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Cognitive impairment has been reported in people living with HIV-1 (PLWH) with prior syphilis, while PLWH who present with incident syphilis have reduced blood CD4 T-lymphocyte and elevated HIV-1 RNA levels. However, the clinical, virological and neurocognitive effects of syphilis during acute HIV-1 (AHI) remain unknown. MethodsPre-antiretroviral therapy laboratory outcomes and neurocognitive performance in a four-test battery in the SEARCH10/RV254 AHI cohort were compared according to syphilis status, determined by serum Treponema pallidum haemagglutination (TPHA), Venereal Disease Research Laboratory (VDRL) and syphilis treatment history. Impaired cognitive performance was defined as having z-scores ≤ À1 in at least two tests or ≤ À2 in at least one test. ResultsOut of 595 AHI participants (97% male, median age of 26 years and estimated duration of HIV-1 infection of 19 days), 119 (20%) had history of syphilis (TPHA-positive), of whom 51 (9%) had untreated syphilis (TPHA-positive/VDRL-positive/without prior treatment). Compared with those without syphilis (TPHA-negative), individuals with untreated syphilis had higher CD8 Tlymphocyte levels but not higher plasma HIV-1 RNA or lower CD4 T-lymphocyte levels. Taking into account estimated duration of HIV-1 infection (P < 0.001), and later Fiebig stages (III-V) (P < 0.001), those with untreated syphilis had higher CD8 T-lymphocyte levels (P = 0.049). Individuals with any syphilis (TPHA-positive), but not untreated syphilis, had higher odds of impaired cognitive performance than those without (P = 0.002). ConclusionsDuring AHI, individuals with any history of syphilis (TPHA-positive) had poorer cognitive performance than those without syphilis. However, syphilis was not associated with worsened HIV disease measures as described in chronic infection.

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Section: Discussionsupporting

confidence: 89%

Section: Study Design and Participantsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical and laboratory impact of concomitant syphilis infection during acute HIV

et al. 2021

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“…As has been previously reported in this cohort [6,7,37], multiple soluble markers of inflammation were differentially expressed in CSF during acute HIV-1 infection. Among a panel of 44 pro-inflammatory cytokines and biomarkers measured by Luminex and ELISA in this subset of nine individuals, IL-10 (P<0.01), IP-10 (P<0.01), neopterin (P<0.01) and sCD163 (P<0.05) were ~2-5-fold elevated in CSF compared to PWOH.…”

Section: Plos Pathogenssupporting

confidence: 82%

Cerebrospinal fluid CD4+ T cell infection in humans and macaques during acute HIV-1 and SHIV infection

et al. 2021

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HIV-1 replication within the central nervous system (CNS) impairs neurocognitive function and has the potential to establish persistent, compartmentalized viral reservoirs. The origins of HIV-1 detected in the CNS compartment are unknown, including whether cells within the cerebrospinal fluid (CSF) produce virus. We measured viral RNA+ cells in CSF from acutely infected macaques longitudinally and people living with early stages of acute HIV-1. Active viral transcription (spliced viral RNA) was present in CSF CD4+ T cells as early as four weeks post-SHIV infection, and among all acute HIV-1 specimens (N = 6; Fiebig III/IV). Replication-inactive CD4+ T cell infection, indicated by unspliced viral RNA in the absence of spliced viral RNA, was even more prevalent, present in CSF of >50% macaques and human CSF at ~10-fold higher frequency than productive infection. Infection levels were similar between CSF and peripheral blood (and lymph nodes in macaques), indicating comparable T cell infection across these compartments. In addition, surface markers of activation were increased on CSF T cells and monocytes and correlated with CSF soluble markers of inflammation. These studies provide direct evidence of HIV-1 replication in CD4+ T cells and broad immune activation in peripheral blood and the CNS during acute infection, likely contributing to early neuroinflammation and reservoir seeding. Thus, early initiation of antiretroviral therapy may not be able to prevent establishment of CNS viral reservoirs and sources of long-term inflammation, important targets for HIV-1 cure and therapeutic strategies.

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“…Peripherally, CD8 + T cells exert some control of viral infection by cytotoxicity-mediated killing (5). In one study, these cytotoxic CD8 + and helper CD4 + T lymphocytes independently correlated directly with HIV RNA levels in cerebrospinal fluid (CSF) and in plasma during acute infection, suggesting that peripheral immune response may modulate CNS viral infection (6). However, the severity of CNS lesions did not correlate with the corresponding plasma viral load, despite the correlation between CSF and plasma viral loads (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Increased IL-6 expression precedes reliable viral detection in the rhesus macaque brain during acute SIV infection

Gopalakrishnan¹,

Aïd²,

Mercado³

et al. 2021

JCI Insight

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Distribution of Human Immunodeficiency Virus (HIV) Ribonucleic Acid in Cerebrospinal Fluid and Blood Is Linked to CD4/CD8 Ratio During Acute HIV

Abstract: The degree of central nervous system penetration by HIV at acute infection, measured by the viral load difference between plasma and cerebrospinal fluid, is highly variable and correlates with CD4/CD8 ratio, suggesting an underlying modifying role by individual immune response.

Cited by 18 publications

References 40 publications

Clinical and laboratory impact of concomitant syphilis infection during acute HIV

Clinical and laboratory impact of concomitant syphilis infection during acute HIV

Cerebrospinal fluid CD4+ T cell infection in humans and macaques during acute HIV-1 and SHIV infection

Increased IL-6 expression precedes reliable viral detection in the rhesus macaque brain during acute SIV infection

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