Addendum: Immune clearance of highly pathogenic SIV infection

Hansen, Scott G.; Piatak, Michael; Ventura, Abigail B.; Hughes, Colette M.; Gilbride, Roxanne M.; Ford, Julia C.; Oswald, Kelli; Shoemaker, Rebecca; Li, Yuan; Lewis, Matthew S.; Gilliam, Awbrey N.; Xu, Guangwu; Whizin, Nathan; Burwitz, Benjamin J.; Planer, Shannon L.; Turner, John M.; Legasse, Alfred W.; Axthelm, Michael K.; Nelson, Jay A.; Früh, Klaus; Sacha, Jonah B.; Estes, Jacob D.; Keele, Brandon F.; Edlefsen, Paul T.; Lifson, Jeffrey D.; Picker, Louis J.

doi:10.1038/nature22984

Cited by 44 publications

(47 citation statements)

References 2 publications

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“…Plasma SIV RNA was measured using a gag-targeted quantitative real-time/digital PCR method with 6 replicate reactions analyzed per extracted sample for an assay threshold of 30 SIV RNA copies/ml (44). Cell-associated SIV RNA and DNA were measured by quantitative hybrid real-time/digital RT-PCR and PCR assays (45,46).…”

Section: Viral Load Monitoringmentioning

confidence: 99%

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

et al. 2020

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Long-term delivery of anti-HIV monoclonal antibodies using adeno-associated virus (AAV) holds promise for the prevention and treatment of HIV infection. We previously reported that after receiving a single administration of AAV vector coding for anti-SIV antibody 5L7, monkey 84-05 achieved high levels of AAV-delivered 5L7 IgG1 in vivo which conferred sterile protection against six successive, escalating dose, intravenous challenges with highly infectious, highly pathogenic SIVmac239, including a final challenge with 10 animal infectious doses (1). Here we report that monkey 84-05 has successfully maintained 240-350 µg/ml of anti-SIV antibody 5L7 for over 6 years. Approximately 2% of the circulating IgG in this monkey is this one monoclonal antibody. This monkey generated little or no anti-drug antibodies (ADA) to the AAV-delivered antibody for the duration of the study. Due to the nature of the high-dose challenge used and in order to rule out a potential low-level infection not detected by regular viral loads, we have used ultrasensitive techniques to detect cell-associated viral DNA and RNA in PBMCs from this animal. In addition, we have tested serum from 84-05 by ELISA against overlapping peptides spanning the whole envelope sequence for SIVmac239 (PepScan) and against recombinant p27 and gp41 proteins. No reactivity has been detected in the ELISAs indicating the absence of naturally arising anti-SIV antibodies; moreover, the ultrasensitive cell-associated viral tests yielded no positive reaction. We conclude that macaque 84-05 was effectively protected and remained uninfected. Our data show that durable, continuous antibody expression can be achieved after one single administration of AAV and support the potential for lifelong protection against HIV from a single vector administration.

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Section: Viral Load Monitoringmentioning

confidence: 99%

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

et al. 2020

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“…Second, CD8 cells are essential to the eradication of residual HIV-1 reservoirs after ART initiation (23)(24)(25)(26). Third, CD8 cells can be induced to enhance the efficacy of vaccination (27), as reported recently in nonhuman primate models (28,29). To this end, it is worthwhile to take a step back and examine the dynamics and correlates of CD8 counts before ART initiation, especially in regions where such data remain sparse.…”

Section: D8mentioning

confidence: 99%

Dynamics and Correlates of CD8 T-Cell Counts in Africans with Primary Human Immunodeficiency Virus Type 1 Infection

Prentice

Price

et al. 2016

J Virol

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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. IMPORTANCELongitudinal 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 indepth 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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“…SIV viral RNA (vRNA) levels in plasma were determined by real-time RT-PCR using the ABI Prism 7900 sequence detection system (Applied Biosystems) as previously described (79). Primer pairs for the assay corresponded to the forward nucleotides 1181 to 1208 and reverse nucleotides1338 to 1317 of the SIV mac239 gag gene (80).…”

Section: Methodsmentioning

confidence: 99%

Simian Immunodeficiency Virus Infection of Rhesus Macaques Results in Delayed Zika Virus Clearance

Vinton

Magaziner

Dowd

et al. 2019

mBio

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Flaviviruses are controlled by adaptive immune responses but are exquisitely sensitive to interferon-stimulated genes (ISGs). How coinfections, particularly simian immunodeficiency viruses (SIVs), that induce robust ISG signatures influence flavivirus clearance and pathogenesis is unclear. Here, we studied how Zika virus (ZIKV) infection is modulated in SIV-infected nonhuman primates. We measured ZIKV replication, cellular ZIKV RNA levels, and immune responses in non-SIV-infected and SIV-infected rhesus macaques (RMs), which we infected with ZIKV. Coinfected animals had a 1-to 2-day delay in peak ZIKV viremia, which was 30% of that in non-SIV-infected animals. However, ZIKV viremia was significantly prolonged in SIVpositive (SIV ϩ ) RMs. ISG levels at the time of ZIKV infection were predictive for lower ZIKV viremia in the SIV ϩ RMs, while prolonged ZIKV viremia was associated with muted and delayed adaptive responses in SIV ϩ RMs. IMPORTANCE Immunocompromised individuals often become symptomatic with infections which are normally fairly asymptomatic in healthy individuals. The particular mechanisms that underlie susceptibility to coinfections in human immunodeficiency virus (HIV)-infected individuals are multifaceted. ZIKV and other flaviviruses are sensitive to neutralizing antibodies, whose production can be limited in HIV-infected individuals but are also sensitive to type I interferons, which are expressed at high levels in HIV-infected individuals. Data in this study highlight how individual components of the innate and adaptive immune responses which become perturbed in HIVinfected individuals influence ZIKV infection.

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Addendum: Immune clearance of highly pathogenic SIV infection

Cited by 44 publications

References 2 publications

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

Long-Term Delivery of an Anti-SIV Monoclonal Antibody With AAV

Dynamics and Correlates of CD8 T-Cell Counts in Africans with Primary Human Immunodeficiency Virus Type 1 Infection

Simian Immunodeficiency Virus Infection of Rhesus Macaques Results in Delayed Zika Virus Clearance

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