Immune correlates of HIV-1 reservoir cell decline in early-treated infants

Hartana, Ciputra Adijaya; García-Broncano, Pilar; Rassadkina, Yelizaveta; Lian, Xiaodong; Jiang, Chenyang; Einkauf, Kevin; Maswabi, Kenneth; Ajibola, Gbolahan; Moyo, Sikhulile; Mohammed, Terence; Maphorisa, Comfort; Makhema, Joseph; Yuki, Yuko; Martin, Maureen P.; Bennett, Kara; Jean‐Philippe, Patrick; Viard, Mathias; Hughes, Michael D.; Powis, Kathleen M.; Carrington, Mary; Lockman, Shahin; Gao, Ce; Yu, Xu G.; Kuritzkes, Daniel R.; Shapiro, Roger; Lichterfeld, Mathias

doi:10.1016/j.celrep.2022.111126

Cited by 16 publications

(9 citation statements)

References 58 publications

(74 reference statements)

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“…Longitudinal analysis of the proviral reservoir conducted over the period of 24 months showed a decline in the size of the reservoir over time, which was more pronounced for the intact proviruses than the defective proviruses and resulted in a disproportionate over-representation of defective proviruses after more advanced analysis time points. These findings are consistent with earlier studies evaluating the longitudinal changes in the proviral reservoir in adults [ 27 – 29 ] and in neonates from Botswana [ 3 , 30 ]. We propose that the more pronounced decline of intact proviruses might be because cells harboring intact HIV-1 may be more vulnerable to host immune responses, arguably because such cells can produce complete viral particles that may be sensed by host immune recognition mechanisms.…”

Section: Discussionsupporting

confidence: 93%

“…A substantial proportion (46%) of infected infants and children do not have access to antiretroviral treatment (ART) [ 2 ], and in those who do, long-term toxicity may be a concern, as well as insufficient adherence to antiretroviral drugs. If successful in durably suppressing HIV-1 replication, ART in children is highly effective in restoring immune function and normalizing many of the immune perturbations that occur in infected infants [ 3 ]. However, even when initiated extremely early or within hours after birth, ART does not eliminate all HIV-1 infected cells, and a persisting reservoir of virally infected cells, frequently termed “HIV-1 reservoir cells” can persist life-long [ 4 – 9 ].…”

Section: Introductionmentioning

confidence: 99%

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HIV-1 reservoir evolution in infants infected with clade C from Mozambique

Koofhethile¹,

Rinaldi²,

Rassadkina³

et al. 2023

International Journal of Infectious Diseases

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

HIV-1 reservoir evolution in infants infected with clade C from Mozambique

Koofhethile¹,

Rinaldi²,

Rassadkina³

et al. 2023

International Journal of Infectious Diseases

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“…Longitudinal analysis of NK cells revealed that the perturbations seen in HEI when compared to HEU at pre-ART initiation were diminished during the first 18 months of life. It has been noted in pediatric and adult studies that early initiation of ART and maintenance of viral suppression leads to at least a partial correction of persistent activation and inflammation [45][46][47]. a majority of the HEI in the TARA cohort had suboptimal adherence to treatment and were viremic throughout the follow up period, but our data demonstrates that many innate cellular phenotypes and subsets normalized to levels of that observed in HEU regardless of virus suppression status.…”

Section: Discussionsupporting

confidence: 42%

Longitudinal analysis of innate immune system in infants with perinatal HIV infection until 18 months of age

Dinh,

de Armas,

Pallikkuth

et al. 2023

Preprint

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With the advent of antiretroviral therapy (ART), perinatal HIV infection is declining globally but prevalence in Sub-Saharan Africa is still greater than other nations. The relationship of HIV replication in early infancy and the developing immune system is not well understood. In this study, we investigated cellular components of the innate immune system including Natural Killer (NK) cells, monocytes, and Dendritic Cells (DC) in a cohort of HIV exposed infected (HEI) and age-matched HIV exposed uninfected (HEU) infants from Mozambique. Study entry was at the first visit after delivery at age 1-2 months for HIV diagnosis and initiation of ART. Phenotypic analysis by multi-parameter flow cytometry revealed an expansion of total NK cells and the dysfunctional, CD56-CD16+, NK cell subset; increased activation in monocytes and DC; and higher levels of inflammatory homing receptor CCR5 on circulating DC subsets in the HEI infants. NKG2A, an inhibitory receptor for NK cytolytic function, was reduced in HEI compared to HEU and positively correlated with pre-ART viral load (VL) while expression of CCR2, the inflammatory homing receptor, on NK was negatively correlated with VL. Other subsets exhibited positive correlations with VL including the frequency of intermediate monocytes amongst total monocytes. Longitudinal analysis of VL indicated suboptimal ART adherence in HEI. Regardless of level of viral suppression achieved, the frequencies of specific innate immune subsets in HEI were normalized to HEU by 18m. These data support the notion that in early life, NK cells play a role in virus control and should be explored for functional attributes that are effective against HIV at this time during development. Overall, our study provides high resolution overview of the innate immune system during perinatal HIV infection.Author SummaryVertical transmission of HIV has been reduced globally in recent years, however in utero exposure and acquisition of HIV continues to occur, especially in sub-Saharan Africa. Immediate ART initiation is recommended in infants diagnosed with HIV, but adherence is often suboptimal due to behavioral and sociological challenges. The impacts of perinatal HIV infection and ART on the developing immune system in infants are still unclear. Here, we evaluated a cohort of HIV exposed infected infants, and age-matched HIV exposed uninfected infants from Mozambique at pre-ART (age 1-2m) and post-ART longitudinally (up to 18m) specifically to compare the innate immune cellular components. We found that circulating innate immune cells including Natural Killer (NK) cells, monocytes, and Dendritic Cells (DC) exhibited altered distributions and more activated (inflammatory) phenotypes at pre-ART in infants with HIV suggesting the presence of a virus specific immune response. Despite suboptimal ART adherence in the cohort, differences in innate immune subsets between infected (suppressed and unsuppressed) and uninfected were not observed longitudinally pointing to normalized immune development despite HIV infection. Our study provides new insights into the early innate immune response during perinatal HIV.

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“…When there were no HIV-1 amplification products detectable, results were reported as LOD and calculated as 0.5 copies per maximum number of cells analyzed without target identification. Amplification products were subjected to Illumina MiSeq sequencing, and our computational pipeline was used to distinguish intact and defective sequences as described before ( 5 , 32 ). Monogram Biosciences performed neutralization assays for monoclonal antibodies (mAbs; PhenoSense mAb) on plasma collected at time of virologic failure and env amplicons from full-length intact proviruses at baseline (usually from birth).…”

Section: Methodsmentioning

confidence: 99%

Broadly neutralizing antibody treatment maintained HIV suppression in children with favorable reservoir characteristics in Botswana

et al. 2023

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Broadly neutralizing antibodies (bNAbs) may provide an alternative to standard antiretroviral treatment (ART) for controlling HIV-1 replication and may have immunotherapeutic effects against HIV-1 reservoirs. We conducted a prospective clinical trial with two HIV-1 bNAbs (VRC01LS and 10-1074) in children ( n = 25) who had previously initiated small-molecule ART treatment before 7 days of age and who continued treatment for at least 96 weeks. Both bNAbs were dosed intravenously every 4 weeks, overlapping with ART for at least 8 weeks and then continued for up to 24 weeks or until detectable viremia of HIV-1 RNA rose above 400 copies per milliliter in the absence of ART. Eleven (44%) children maintained HIV-1 RNA below 400 copies per milliliter through 24 weeks of bNAb-only treatment; 14 (56%) had detectable viremia above 400 copies per milliliter at a median of 4 weeks. Archived HIV-1 provirus susceptible to 10-1074, lower birth HIV-1 DNA reservoir in peripheral blood mononuclear cells, sustained viral suppression throughout early life, and combined negative qualitative HIV-1 DNA polymerase chain reaction and negative HIV-1 serology at entry were associated with maintaining suppression on bNAbs alone. This proof-of-concept study suggests that bNAbs may represent a promising treatment modality for infants and children living with HIV-1. Future studies using newer bNAb combinations with greater breadth and potency are warranted.

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Immune correlates of HIV-1 reservoir cell decline in early-treated infants

Cited by 16 publications

References 58 publications

HIV-1 reservoir evolution in infants infected with clade C from Mozambique

HIV-1 reservoir evolution in infants infected with clade C from Mozambique

Longitudinal analysis of innate immune system in infants with perinatal HIV infection until 18 months of age

Broadly neutralizing antibody treatment maintained HIV suppression in children with favorable reservoir characteristics in Botswana

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