Association of HIV neutralizing antibody with lower viral load after treatment interruption in a prospective trial (A5170)

ABSTRACT In individuals with HIV-1 infection, depletion of CD4 + T cells is often accompanied by a malfunction of CD8 + T cells that are persistently activated and/or exhausted. While the dynamics and correlates of CD4 counts have been well documented, the same does not apply to CD8 counts. Here, we examined the CD8 counts in a cohort of 497 Africans with primary HIV-1 infection evaluated in monthly to quarterly follow-up visits for up to 3 years in the absence of antiretroviral therapy. Statistical models revealed that (i) CD8 counts were relatively steady in the 3- to 36-month period of infection and similar between men and women; (ii) neither geography nor heterogeneity in the HIV-1 set-point viral load could account for the roughly 10-fold range of CD8 counts in the cohort ( P > 0.25 in all tests); and (iii) factors independently associated with relatively high CD8 counts included demographics (age ≤ 40 years, adjusted P = 0.010) and several human leukocyte antigen class I (HLA-I) alleles, including HLA-A*03:01 ( P = 0.013), B*15:10 ( P = 0.007), and B*58:02 ( P < 0.001). Multiple sensitivity analyses provided supporting evidence for these novel relationships. Overall, these findings suggest that factors associated with the CD8 count have little overlap with those previously reported for other HIV-1-related outcome measures, including viral load, CD4 count, and CD4/CD8 ratio. IMPORTANCE Longitudinal data from 497 HIV-1 seroconverters allowed us to systematically evaluate the dynamics and correlates of CD8 + T-cell counts during untreated primary HIV-1 infection in eastern and southern Africans. Our findings suggest that individuals with certain HLA-I alleles, including A*03 (exclusively A*03:01), persistently maintain relatively high CD8 counts following HIV-1 infection, a finding which may offer an intriguing explanation for the recently reported, negative association of A*03 with HIV-1-specific, broadly neutralizing antibody responses. In future studies, attention to HLA-I genotyping data may benefit in-depth understanding of both cellular and humoral immunity, as well as the intrinsic balances of these types of immunity, especially in settings where there is emerging evidence of antagonism between the two arms of adaptive immunity.

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The Characterization of Disease Severity Associated IgG Subclasses Response in COVID-19 Patients

Frontiers in Immunology ◽

10.3389/fimmu.2021.632814 ◽

2021 ◽

Vol 12 ◽

Author(s):

Huanle Luo ◽

Tingting Jia ◽

Jiamin Chen ◽

Shike Zeng ◽

Zengzhao Qiu ◽

...

Keyword(s):

Viral Load ◽

Disease Severity ◽

Young Patients ◽

Neutralizing Antibody ◽

Igg Subclasses ◽

Nasopharyngeal Swab ◽

Obvious Effect ◽

Old Patients ◽

Biological Sex ◽

Specific Igg

Increasing evidence suggests that dysregulated immune responses are associated with the clinical outcome of coronavirus disease 2019 (COVID-19). Nucleocapsid protein (NP)-, spike (S)-, receptor binding domain (RBD)- specific immunoglobulin (Ig) isotypes, IgG subclasses and neutralizing antibody (NAb) were analyzed in 123 serum from 63 hospitalized patients with severe, moderate, mild or asymptomatic COVID-19. Mild to modest correlations were found between disease severity and antigen specific IgG subclasses in serum, of which IgG1 and IgG3 were negatively associated with viral load in nasopharyngeal swab. Multiple cytokines were significantly related with antigen-specific Ig isotypes and IgG subclasses, and IL-1β was positively correlated with most antibodies. Furthermore, the old patients (≥ 60 years old) had higher levels of chemokines, increased NAb activities and SARS-CoV-2 specific IgG1, and IgG3 responses and compromised T cell responses compared to the young patients (≤ 18 years old), which are related with more severe cases. Higher IgG1 and IgG3 were found in COVID-19 patients with comorbidities while biological sex had no effect on IgG subclasses. Overall, we have identified diseases severity was related to higher antibodies, of which IgG subclasses had weakly negative correlation with viral load, and cytokines were significantly associated with antibody response. Further, advancing age and comorbidities had obvious effect on IgG1 and IgG3.

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Re-boost immunizations with the peptide-based therapeutic HIV vaccine, Vacc-4x, restores geometric mean viral load set-point during treatment interruption

PLoS ONE ◽

10.1371/journal.pone.0210965 ◽

2019 ◽

Vol 14 (1) ◽

pp. e0210965 ◽

Cited By ~ 3

Author(s):

Jürgen K. Rockstroh ◽

David Asmuth ◽

Giuseppe Pantaleo ◽

Bonaventura Clotet ◽

Daniel Podzamczer ◽

...

Keyword(s):

Viral Load ◽

Geometric Mean ◽

Treatment Interruption ◽

Hiv Vaccine ◽

Set Point ◽

Viral Load Set Point

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Breadth of Neutralizing Antibody Response to Human Immunodeficiency Virus Type 1 Is Affected by Factors Early in Infection but Does Not Influence Disease Progression

Journal of Virology ◽

10.1128/jvi.01149-09 ◽

2009 ◽

Vol 83 (19) ◽

pp. 10269-10274 ◽

Cited By ~ 133

Author(s):

Anne Piantadosi ◽

Dana Panteleeff ◽

Catherine A. Blish ◽

Jared M. Baeten ◽

Walter Jaoko ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Viral Load ◽

Disease Progression ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibody ◽

Subtype B ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The determinants of a broad neutralizing antibody (NAb) response and its effect on human immunodeficiency virus type 1 (HIV-1) disease progression are not well defined, partly because most prior studies of a broad NAb response were cross-sectional. We examined correlates of NAb response breadth among 70 HIV-infected, antiretroviral-naïve Kenyan women from a longitudinal seroincident cohort. NAb response breadth was measured 5 years after infection against five subtype A viruses and one subtype B virus. Greater NAb response breadth was associated with a higher viral load set point and greater HIV-1 env diversity early in infection. However, greater NAb response breadth was not associated with a delayed time to a CD4+ T-cell count of <200, antiretroviral therapy, or death. Thus, a broad NAb response results from a high level of antigenic stimulation early in infection, which likely accounts for prior observations that greater NAb response breadth is associated with a higher viral load later in infection.

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Viral Dynamics during Structured Treatment Interruptions of Chronic Human Immunodeficiency Virus Type 1 Infection

Journal of Virology ◽

10.1128/jvi.76.3.968-979.2002 ◽

2002 ◽

Vol 76 (3) ◽

pp. 968-979 ◽

Cited By ~ 39

Author(s):

Simon D. W. Frost ◽

Javier Martinez-Picado ◽

Lidia Ruiz ◽

Bonaventura Clotet ◽

Andrew J. Leigh Brown

Keyword(s):

Human Immunodeficiency Virus ◽

Viral Load ◽

Immune Responses ◽

Treatment Interruption ◽

Viral Rebound ◽

Viral Dynamics ◽

Viral Loads ◽

Treatment Interruptions ◽

Immunodeficiency Virus

ABSTRACT Although antiviral agents which block human immunodeficiency virus (HIV) replication can result in long-term suppression of viral loads to undetectable levels in plasma, long-term therapy fails to eradicate virus, which generally rebounds after a single treatment interruption. Multiple structured treatment interruptions (STIs) have been suggested as a possible strategy that may boost HIV-specific immune responses and control viral replication. We analyze viral dynamics during four consecutive STI cycles in 12 chronically infected patients with a history (>2 years) of viral suppression under highly active antiretroviral therapy. We fitted a simple model of viral rebound to the viral load data from each patient by using a novel statistical approach that allows us to overcome problems of estimating viral dynamics parameters when there are many viral load measurements below the limit of detection. There is an approximate halving of the average viral growth rate between the first and fourth STI cycles, yet the average time between treatment interruption and detection of viral loads in the plasma is approximately the same in the first and fourth interruptions. We hypothesize that reseeding of viral reservoirs during treatment interruptions can account for this discrepancy, although factors such as stochastic effects and the strength of HIV-specific immune responses may also affect the time to viral rebound. We also demonstrate spontaneous drops in viral load in later STIs, which reflect fluctuations in the rates of viral production and/or clearance that may be caused by a complex interaction between virus and target cells and/or immune responses.

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IL-6 and IL-10 Levels, Rather Than Viral Load and Neutralizing Antibody Titers, Determine the Fate of Patients With Severe Fever With Thrombocytopenia Syndrome Virus Infection in South Korea

Frontiers in Immunology ◽

10.3389/fimmu.2021.711847 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jeong Rae Yoo ◽

Tae-Jin Kim ◽

Sang Taek Heo ◽

Kyung-Ah Hwang ◽

Hyunjoo Oh ◽

...

Keyword(s):

Viral Load ◽

Close Contact ◽

Multiorgan Failure ◽

Severe Disease ◽

Elevated Serum ◽

Gastrointestinal Symptoms ◽

Neutralizing Antibody ◽

Haemaphysalis Longicornis ◽

Antibody Titers ◽

Severe Fever

Severe fever with thrombocytopenia syndrome (SFTS) is a new tick-borne viral disease, and most SFTS virus (SFTSV) infections occur via bites from the tick Haemaphysalis longicornis; however, SFTSV transmission can also occur through close contact with an infected patient. SFTS is characterized by acute high fever, thrombocytopenia, leukopenia, elevated serum hepatic enzyme levels, gastrointestinal symptoms, and multiorgan failure and has a 16.2 to 30% mortality rate. In this study, we found that age, dyspnea rates, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase, multiorgan dysfunction score (MODS), viral load, IL-6 levels, and IL-10 levels were higher in patients with fatal disease than in patients with nonfatal disease during the initial clinical course of SFTS. In addition, we found that IL-6 and IL-10 levels, rather than viral load and neutralizing antibody titers, in patients with an SFTSV infection strongly correlated with outcomes (for severe disease with an ultimate outcome of recovery or death).

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Differential Association of Viral Dynamics With Disease Severity Depending on Patients’ Age Group in COVID-19

Frontiers in Microbiology ◽

10.3389/fmicb.2021.712260 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuri Kim ◽

Shinhyea Cheon ◽

Hyeongseok Jeong ◽

Uni Park ◽

Na-Young Ha ◽

...

Keyword(s):

Viral Load ◽

Elderly Patients ◽

Disease Severity ◽

Acute Phase ◽

Inflammatory Responses ◽

Severe Disease ◽

Neutralizing Antibody ◽

The Elderly ◽

Clinical Severity ◽

Younger Patients

Despite a clear association of patient’s age with COVID-19 severity, there has been conflicting data on the association of viral load with disease severity. Here, we investigated the association of viral load dynamics with patient’s age and severity of COVID-19 using a set of respiratory specimens longitudinally collected (mean: 4.8 times/patient) from 64 patients with broad distribution of clinical severity and age during acute phase. Higher viral burden was positively associated with inflammatory responses, as assessed by IL-6, C-reactive protein, and lactate dehydrogenase levels in patients’ plasma collected on the same day, primarily in the younger cohort (≤59 years old) and in mild cases of all ages, whereas these were barely detectable in elderly patients (≥60 years old) with critical disease. In addition, viral load dynamics in elderly patients were not significantly different between mild and critical cases, even though more enhanced inflammation was consistently observed in the elderly group when compared to the younger group during the acute phase of infection. The positive correlation of viral load with disease severity in younger patients may explain the increased therapeutic responsiveness to current antiviral drugs and neutralizing antibody therapies in younger patients compared to elderly patients. More careful intervention against aging-associated inflammation might be required to mitigate severe disease progression and reduce fatality in COVID-19 patients more than 60 years old.

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Phospholipid Metabolism Is Associated with HIV Rebound Upon Treatment Interruption

10.1101/2020.12.09.418814 ◽

2020 ◽

Author(s):

Leila B. Giron ◽

Emmanouil Papasavvas ◽

Xiangfan Yin ◽

Aaron R. Goldman ◽

Hsin-Yao Tang ◽

...

Keyword(s):

Viral Load ◽

Antiretroviral Therapy ◽

Tumor Cells ◽

Treatment Interruption ◽

Phospholipid Metabolism ◽

Biologically Active ◽

Inflammatory Factors ◽

Hiv Latency ◽

Potential Contribution ◽

Viral Rebound

ABSTRACTLipids are biologically active molecules involved in a variety of cellular processes and immunological functions, including inflammation. It was recently shown that phospholipids and their derivatives, lysophospholipids, can reactivate latent (dormant) tumor cells, causing cancer recurrence. However, the potential link between lipids and HIV latency, persistence, and viral rebound after cessation of antiretroviral therapy (ART) has never been investigated. We explored the links between plasma lipids and the burden of HIV during ART. We profiled the circulating lipidome from the plasma of 24 chronically HIV-infected individuals on suppressive ART who subsequently underwent an analytic treatment interruption (ATI) without concurrent immunotherapies. The pre-ATI viral burden was estimated as time-to-viral-rebound and viral load setpoints post-ATI. We found that higher pre-ATI levels of lysophospholipids, including the pro-inflammatory lysophosphatidylcholine, were associated with faster time-to-viral-rebound and higher viral setpoints upon ART cessation. Furthermore, higher pre-ATI levels of the pro-inflammatory byproduct of intestinal lysophosphatidylcholine metabolism, trimethylamine-N-oxide (TMAO), were also linked to faster viral rebound post-ART. Finally, pre-ATI levels of several phosphatidylcholine species (lysophosphatidylcholine precursors) correlated strongly with higher pre-ATI levels of HIV DNA in peripheral CD4+ T cells. Our proof-of-concept data point to phospholipids and lysophospholipids as plausible pro-inflammatory contributors to HIV persistence and rapid post-ART HIV rebound. The potential interplay between phospholipid metabolism and both the establishment and maintenance of HIV latent reservoirs during- and post-ART warrants further investigation.IMPORTANCEThe likelihood of HIV rebound after stopping antiretroviral therapy (ART) is a function of the interplay between the size of HIV reservoirs that persist despite ART and the host immunological and inflammatory factors that modulate these reservoirs. There is a need to comprehensively understand these host factors to develop a strategy to cure HIV infection and prevent viral rebound post-ART. Lipids are important biologically active molecules that are known to mediate several cellular functions, including reactivating latent tumor cells; however, their role in HIV latency, persistence, and post-ART rebound has never been investigated. We observed significant links between higher levels of the pro-inflammatory lysophosphatidylcholine and its intestinal metabolic byproduct, trimethylamine-N-oxide, and both faster time-to-viral rebound and higher viral load setpoint post ART. These data highlight the need for further studies to understand the potential contribution of phosphatidylcholine and lysophosphatidylcholine metabolism in shaping host immunological and inflammatory milieu during- and post-ART.

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