Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection

Muenchhoff, Maximilian; Adland, Emily; Karimanzira, Owen; Crowther, Carol; Pace, Matthew; Csala, Anna; Leitman, Ellen M.; Moonsamy, Angeline; McGregor, Callum; Hurst, Jacob; Groll, Andreas; Mori, Masahiko; Sinmyee, Smruti; Thobakgale, Christina; Tudor‐Williams, Gareth; Prendergast, Andrew J.; Kløverpris, Henrik N.; Roider, Julia; Leslie, Alasdair; Shingadia, Delane; Brits, Thea; Daniels, Samantha; Frater, John; Willberg, Christian; Walker, Bruce D.; Ndung’u, Thumbi; Jooste, Pieter; Moore, Penny L.; Morris, Lynn; Goulder, Philip

doi:10.1126/scitranslmed.aag1048

Cited by 114 publications

(224 citation statements)

References 68 publications

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“…The three VNP individuals described in this study had been infected with HIV-1 for at least 10 years at the time the blood sample was taken, with stable CD4 + T-cell counts and high plasma HIV RNA loads. When compared with three typical (TP) and one rapid progressor (RP) patients, the number of CD4 + T-cells barely declined in the VNPs over this period of time, similar to what have been described for other adult and children VNPs [43, 82–84, 86]. No other significant differences were observed among the VNP and TP patients, including plasma viral load levels and basic virus characteristics such as HIV-1 subtype (all clade B) and coreceptor tropism (all CCR5-tropic viruses).…”

Section: Discussionsupporting

confidence: 77%

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Impaired human immunodeficiency virus type 1 replicative fitness in atypical viremic non-progressor individuals

et al. 2017

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BackgroundProgression rates from initial HIV-1 infection to advanced AIDS vary significantly among infected individuals. A distinct subgroup of HIV-1-infected individuals—termed viremic non-progressors (VNP) or controllers—do not seem to progress to AIDS, maintaining high CD4+ T cell counts despite high levels of viremia for many years. Several studies have evaluated multiple host factors, including immune activation, trying to elucidate the atypical HIV-1 disease progression in these patients; however, limited work has been done to characterize viral factors in viremic controllers.MethodsWe analyzed HIV-1 isolates from three VNP individuals and compared the replicative fitness, near full-length HIV-1 genomes and intra-patient HIV-1 genetic diversity with viruses from three typical (TP) and one rapid (RP) progressor individuals.ResultsViremic non-progressors and typical patients were infected for >10 years (range 10–17 years), with a mean CD4+ T-cell count of 472 cells/mm3 (442–529) and 400 cells/mm3 (126–789), respectively. VNP individuals had a less marked decline in CD4+ cells (mean −0.56, range −0.4 to −0.7 CD4+/month) than TP patients (mean −10.3, −8.2 to −13.1 CD4+/month). Interestingly, VNP individuals carried viruses with impaired replicative fitness, compared to HIV-1 isolates from the TP and RP patients (p < 0.05, 95% CI). Although analyses of the near full-length HIV-1 genomes showed no clear patterns of single-nucleotide polymorphisms (SNP) that could explain the decrease in replicative fitness, both the number of SNPs and HIV-1 population diversity correlated inversely with the replication capacity of the viruses (r = −0.956 and r = −0.878, p < 0.01, respectively).ConclusionIt is likely that complex multifactorial parameters govern HIV-1 disease progression in each individual, starting with the infecting virus (phenotype, load, and quasispecies diversity) and the intrinsic ability of the host to respond to the infection. Here we analyzed a subset of viremic controller patients and demonstrated that similar to the phenomenon observed in patients with a discordant response to antiretroviral therapy (i.e., high CD4+ cell counts with detectable plasma HIV-1 RNA load), reduced viral replicative fitness seems to be linked to slow disease progression in these antiretroviral-naïve individuals.Electronic supplementary materialThe online version of this article (doi:10.1186/s12981-017-0144-0) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 77%

“…Interestingly, viremic pediatric nonprogressor patients with high CD4 + T cell counts seem to be more common than adults VNP individuals [86]. Is it possible that VNP patients are more common than what we originally thought?…”

Section: Discussionmentioning

confidence: 99%

Impaired human immunodeficiency virus type 1 replicative fitness in atypical viremic non-progressor individuals

et al. 2017

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“…Many scenarios of well-controlled infection or disease support a skewing of SIV/HIV infection towards effector memory CD4 + T cells that may be more dispensable, resulting in a more protected CD4 + T cell memory pool. These include non-pathogenic infection of nonhuman primates such as sooty mangabeys and African green monkeys [33], human LTNP/ECs [34, 35], post-treatment controllers [36], and unique groups - adult viraemic nonprogressors [37] and paediatric nonprogressors [38] - who have high viral loads, low immune activation and conserved CD4 + T cell counts. Furthermore, the expression of CXCR6 is critical for antigen-specific memory liver NK cells [39] , and CXCX6 correlates with CD56 expression on T cells which associates with cytotoxic potential [32].…”

Section: Discussionmentioning

confidence: 99%

CXCR6 gene characterization in two ethnically distinct South African populations and association with viraemic disease control in HIV-1-infected black South African individuals

Picton

Paximadis

Chaisson

et al. 2017

Clinical Immunology

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CXCR6 genetic variation was described for HIV-1-uninfected black (n=41) and Caucasian (n=40) South Africans. We also investigated the CXCR6 rs2234358 and rs2234355 single nucleotide polymorphisms in HIV-1 disease control in 124 HIV-1-infected drug-naïve black individuals [elite controllers (n=11), viraemic controllers (VCs, n=30), high viral load long-term nonprogressors (HVL LTNPs, n=11) and progressors (n=72)] compared to healthy controls (HCs; n=232). The rs2234358-T allele was underrepresented in VCs (40.0%) compared to HCs (59%, P=0.006), HVL LTNPs (72.7%, P=0.012) and progressors (59%, P=0.014). The rs2234358-TT genotype was underrepresented in VCs (7%) compared to progressors (32%; OR=6.57, P=0.006) and HCs (35%; OR=7.18, P=0.001, Pbonferroni=0.034). The rs2234355-GA genotype was overrepresented in VCs (80%) compared to HCs (50.4%; OR=0.25, P=0.003) and progressors (29.17%; OR=0.10, P=3.8x10−5, Pbonferroni=0.001). The combination of rs2234355-GA in the absence of rs2234358-TT was overrepresented in VCs (80%) compared to HCs (32.6%, OR=0.12, P=1x10−6, Pbonferroni =3.4x10−5) and to progressors (16.7%; OR=0.05, P<1x10−8, Pbonferroni <1x10−7).

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“…Of interest, the proportion of chronically infected children who develop broad and potent neutralizing antibodies is considerably higher, with 70% of children mounting responses that are equivalently broad to the top 20% of adults infected with the same subtype of HIV-1 (Fig. 2) [30]. These bNAb responses in children have been reported to develop earlier than is common in adults, in some cases within the first 2 years of life [31, 32].…”

Section: Broadly Neutralizing Antibodiesmentioning

confidence: 99%

“…These include duration of infection, high viral load, viral diversity and low CD4 T cell counts [26–29, 64]. In children, the high levels of bNAbs are also associated with long-term and high levels of viremia [30]. These associations highlight the substantial antigenic stimulation generally required to drive the high level of somatic hypermutation associated with bNAbs, though there are cases of viral controllers who develop bNAbs [65].…”

Section: Broadly Neutralizing Antibodiesmentioning

confidence: 99%

The Neutralizing Antibody Response to the HIV-1 Env Protein

Moore

2018

CHR

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Objective: Background:A vaccine able to elicit broadly neutralizing antibodies capable of blocking infection by global viruses has not been achieved, and remains a key public health challenge. Objective: Objective:During infection, a robust strain-specific neutralizing response develops in most people, but only a subset of infected people develop broadly neutralizing antibodies. Understanding how and why these broadly neutralizing antibodies develop has been a focus of the HIV-1 vaccine field for many years, and has generated extraordinary insights into the neutralizing response to HIV-1 infection. Results: This review describes the features, targets and developmental pathways of early strain-specific antibodies and later broadly neutralizing antibodies, and explores the reasons such broad antibodies are not more commonly elicited during infection. Conclusion: The insights from these studies have been harnessed for the development of pioneering new vaccine approaches that seek to drive B cell maturation towards breadth. Overall, this review describes how findings from infected donors have impacted on active and passive immunization approaches that seek to prevent HIV-1 infection.

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Nonprogressing HIV-infected children share fundamental immunological features of nonpathogenic SIV infection

Cited by 114 publications

References 68 publications

Impaired human immunodeficiency virus type 1 replicative fitness in atypical viremic non-progressor individuals

Impaired human immunodeficiency virus type 1 replicative fitness in atypical viremic non-progressor individuals

CXCR6 gene characterization in two ethnically distinct South African populations and association with viraemic disease control in HIV-1-infected black South African individuals

The Neutralizing Antibody Response to the HIV-1 Env Protein

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