There are few cohorts of individuals who have survived infection with HIV-1 for more than 20 years, reported and followed in the literature, and even fewer from Africa. Here we present data on a cohort of subtype C-infected individuals from rural northern Malawi. By sequencing multiple clones from long-term survivors at different time points, and using multiple genotyping approaches, we show that 5 of the 11 individuals are predicted as CXCR4 using (by ≥3/5 predictors) but only one individual is predicted as CXCR4 using by all five algorithms. Using any one genotyping approach overestimates the number of predicted CXCR4 sequences. Patterns of diversity and divergence were variable between the HIV-1 long-term survivors with some individuals showing very small amounts of variation and change, and others showing a greater amount; both patterns are consistent with what has been described in the literature.
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References
1.
ToddJ, GlynnJR, MarstonM, et al.: Time from HIV seroconversion to death: A collaborative analysis of eight studies in six low and middle-income countries before highly active antiretroviral therapy. AIDS, 2007; 21(Suppl. 6):S55–63.
2.
Collaborative Group on AIDS Incubation and HIV Survival including the CASCADE EU Concerted Action: Time from HIV-1 seroconversion to AIDS and death before widespread use of highly-active antiretroviral therapy: A collaborative re-analysis. Lancet, 2000; 355:1131–1137.
3.
LearmontJ, TindallB, EvansL, et al.: Long-term symptomless HIV-1 infection in recipients of blood products from a single donor. Lancet, 1992; 340:863–867.
4.
SaksenaNK, WangB, and DryerWB: Biological and molecular mechanisms in progression and non-progression of HIV disease. AIDS Rev, 2001; 3.
5.
BaileyJR, LassenKG, YangHC, et al.: Neutralizing antibodies do not mediate suppression of human immunodeficiency virus type 1 in elite suppressors or selection of plasma virus variants in patients on highly active antiretroviral therapy. J Virol, 2006; 80:4758–4770.
6.
BlanksonJ, BaileyJ, ThayilS, et al.: Isolation and characterisation of replication-competent human immunodeficiency virus type 1 from a subset of elite suppressors. J Virol, 2007; 81:2508–2518.
7.
AlexanderL, Aquino-DeJesusMJ, ChanM, and AndimanWA: Inhibition of human immunodeficiency virus type 1 (HIV-1) replication by a two-amino-acid insertion in HIV-1 Vif from a nonprogressing mother and child. J Virol, 2002; 76:10533–10539.
8.
YamadaT and IwamotoA: Comparison of proviral accessory genes between long-term nonprogressors and progressors of human immunodeficiency virus type 1 infection. Arch Virol, 2000; 145:1021–1027.
9.
WangB, GeY, PalasanthiranP, et al.: Gene defects clustered at the C-terminus of the vpr gene of HIV-1 in long-term nonprogressing mother and child pair: In vivo evolution of vpr quasispecies in blood and plasma. Virology, 1996; 312:135–150.
10.
MologniD, CitterioP, MenzaghiB, et al.: Vpr and HIV-1 disease progression: R77Q mutation is associated with long-term control of HIV-1 infection in different groups of patients. AIDS, 2006; 20:567–574.
11.
IversenAK, ShpaerEG, RodrigoAG, et al.: Persistence of attenuated rev genes in a human immunodeficiency virus type 1-infected asymptomatic individual. J Virol, 1995; 69:5743–5753.
12.
HuangY, ZhangL, and HoDD: Characterization of gag and pol sequences from long-term survivors of human immunodeficiency virus type 1 infection. Virology, 1998; 240:36–49.
13.
ChoYK and JungYS: High frequency of gross deletions in the 5' LTR and gag regions in HIV type 1-infected long-term survivors treated with Korean red ginseng. AIDS Res Hum Retroviruses, 2008; 24:181–193.
14.
MiguelesSA, OsborneCM, RoyceC, et al.: Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity, 2008; 29:1009–1021.
15.
LopezM, SorianoV, LozanoS, et al.: No major differences in the functional profile of HIV Gag and Nef-specific CD8+ responses between long-term nonprogressors and typical progressors. AIDS Res Hum Retroviruses, 2008; 24:1185–1195.
16.
LambotteO, BoufassaF, MadecY, et al.: HIV controllers: A homogeneous group of HIV-1-infected patients with spontaneous control of viral replication. Clin Infect Dis, 2005; 41:1053–1056.
17.
KloosterboerN, GroeneveldPH, JansenCA, et al.: Natural controlled HIV infection: Preserved HIV-specific immunity despite undetectable replication competent virus. Virology, 2005; 339:70–80.
18.
BirchMR, LearmontJC, DyerWB, et al.: An examination of signs of disease progression in survivors of the Sydney Blood Bank Cohort (SBBC). J Clin Virol, 2001; 22:263–270.
19.
TzitzivacosDB, TiemessenCT, StevensWS, and PapathanasopoulosMA: Viral genetic determinants of nonprogressive HIV type 1 subtype C infection in antiretroviral drug-naive children. AIDS Res Hum Retroviruses, 2009; 25:1141–1148.
20.
ArcharyD, GordonML, GreenTN, et al.: HIV-1 subtype C envelope characteristics associated with divergent rates of chronic disease progression. Retrovirology, 2010; 7:92.
21.
LaeyendeckerO, ReddAD, LutaloT, et al.: Frequency of long-term nonprogressors in HIV-1 seroconverters from Rakai Uganda. J Acquir Immune Defic Syndr, 2009; 52:316–319.
22.
FangG, KuikenC, WeiserB, et al.: Long-term survivors in Nairobi: Complete HIV-1 RNA sequences and immunogenetic associations. J Infect Dis, 2004; 190:697–701.
23.
SeagerI, LeesonMD, CrampinAC, et al.: HIV type 1 mutational patterns in HIV type 1 subtype C-infected long-term survivors in Karonga District Malawi: Further analysis and correction. AIDS Res Hum Retroviruses, 2012; 28:308–313.
24.
McCormackGP, GlynnJR, ClewleyJP, et al.: Emergence of a three codon deletion in gag p17 in HIV type 1 subtype C long-term survivors, and general population spread. AIDS Res Hum Retroviruses, 2006; 22:195–201.
25.
CrampinAC, FloydS, GlynnJR, et al.: Long-term follow-up of HIV-positive and HIV-negative individuals in rural Malawi. AIDS, 2002; 16:1545–1550.
26.
van't WoutAB, KootstraNA, Mulder-KampingaGA, et al.: Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission. J Clin Invest, 1994; 94:2060–2067.
27.
XiaoL, OwenSM, GoldmanI, et al.: CCR5 coreceptor usage of non-syncytium-inducing primary HIV-1 is independent of phylogenetically distinct global HIV-1 isolates: Delineation of consensus motif in the V3 domain that predicts CCR-5 usage. Virology, 1998; 240:83–92.
28.
ZhangLQ, MacKenzieP, ClelandA, et al.: Selection for specific sequences in the external envelope protein of human immunodeficiency virus type 1 upon primary infection. J Virol, 1993; 67:3345–3356.
29.
JekleA, KepplerOT, De ClercqE, et al.: In vivo evolution of human immunodeficiency virus type 1 toward increased pathogenicity through CXCR4-mediated killing of uninfected CD4 T cells. J Virol, 2003; 77:5846–5854.
30.
RichmanDD and BozzetteSA: The impact of the syncytium-inducing phenotype of human immunodeficiency virus on disease progression. J Infect Dis, 1994; 169:968–974.
31.
SchuitemakerH, KootM, KootstraNA, et al.: Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: Progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population. J Virol, 1992; 66:1354–1360.
32.
CeciliaD, KulkarniSS, TripathySP, et al.: Absence of coreceptor switch with disease progression in human immunodeficiency virus infections in India. Virology, 2000; 271:253–258.
33.
ChogeI, CilliersT, WalkerP, et al.: Genotypic and phenotypic characterization of viral isolates from HIV-1 subtype C-infected children with slow and rapid disease progression. AIDS Res Hum Retroviruses, 2006; 22:458–465.
34.
CilliersT, NhlapoJ, CoetzerM, et al.: The CCR5 and CXCR4 coreceptors are both used by human immunodeficiency virus type 1 primary isolates from subtype C. J Virol, 2003; 77:4449–4456.
35.
EngelbrechtS, de VilliersT, SampsonCC, et al.: Genetic analysis of the complete gag and env genes of HIV type 1 subtype C primary isolates from South Africa. AIDS Res Hum Retroviruses, 2001; 17:1533–1547.
36.
MichlerK, ConnellBJ, VenterWD, et al.: Genotypic characterization and comparison of full-length envelope glycoproteins from South African HIV type 1 subtype C primary isolates that utilize CCR5 and/or CXCR4. AIDS Res Hum Retroviruses, 2008; 24:743–751.
37.
MorrisL, CilliersT, BredellH, et al.: CCR5 is the major coreceptor used by HIV-1 subtype C isolates from patients with active tuberculosis. AIDS Res Hum Retroviruses, 2001; 17:697–701.
38.
PapathanasopoulosMA, PatienceT, MeyersTM, et al.: Full-length genome characterization of HIV type 1 subtype C isolates from two slow-progressing perinatally infected siblings in South Africa. AIDS Res Hum Retroviruses, 2003; 19:1033–1037.
39.
PingLH, NelsonJA, HoffmanIF, et al.: Characterization of V3 sequence heterogeneity in subtype C human immunodeficiency virus type 1 isolates from Malawi: Underrepresentation of X4 variants. J Virol, 1999; 73:6271–6281.
40.
ConnellBJ, MichlerK, CapovillaA, et al.: Emergence of X4 usage among HIV-1 subtype C: Evidence for an evolving epidemic in South Africa. AIDS, 2008; 22:896–899.
41.
RaymondS, DelobelP, MavignerM, et al.: Prediction of HIV type 1 subtype C tropism by genotypic algorithms built from subtype B viruses. J Acquir Immune Defic Syndr, 2010; 53:167–175.
42.
McCormackGP, GlynnJR, CrampinAC, et al.: Early evolution of the human immunodeficiency virus type 1 subtype C epidemic in rural Malawi. J Virol, 2002; 76:12890–12899.
43.
StamatakisA: RAxML-VI-HPC: Maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models. Bioinformatics, 2006; 22:2688–2690.
44.
TraversSA, ClewleyJP, GlynnJR, et al.: Timing and reconstruction of the most recent common ancestor of the subtype C clade of human immunodeficiency virus type 1. J Virol, 2004; 78:10501–10506.
45.
KimuraM: A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J Mol Evol, 1980; 16:111–120.
46.
JensenMA, LiFS, van 't WoutAB, et al.: Improved coreceptor usage prediction and genotypic monitoring of R5-to-X4 transition by motif analysis of human immunodeficiency virus type 1 env V3 loop sequences. J Virol, 2003; 77:13376–13388.
47.
JensenMA, CoetzerM, van 't WoutAB, et al.: A reliable phenotype predictor for human immunodeficiency virus type 1 subtype C based on envelope V3 sequences. J Virol, 2006; 80:4698–4704.
48.
LengauerT, SanderO, SierraS, ThielenA, and KaiserR: Bioinformatics prediction of HIV coreceptor usage. Nat Biotechnol, 2007; 25:1407–1410.
49.
CashinK, GrayLR, JakobsenMR, et al.: CoRSeqv3-C: A novel HIV-1 subtype C specific V3 sequence based coreceptor usage prediction algorithm. Retrovirology, 2013; 10:24.
50.
LinN, BecerriC, GiguelF, et al.: Env sequence determinants in CXCR4-using human immunodeficiency virus type 1 subtype C. Virology, 2012; 433(20):296–307.
51.
BjorndalA, SonnerborgA, TscherningC, AlbertJ, and FenyoEM: Phenotypic characteristics of human immunodeficiency virus type 1 subtype C isolates of Ethiopian AIDS patients. AIDS Res Hum Retroviruses, 1999; 15:647–653.
52.
JakobsenMR, CashinK., RocheM, et al.: Longitudinal analysis of CCR5 and CXCR4 usage in a cohort of antiretroviral therapy-naive subjects with progressive HIV-1 subtype C infection. PloS One, 2013; 8(6);65950.
53.
VandekerckhoveLP, WensingAM, KaiserR, et al.: European guidelines on the clinical management of HIV-1 tropism testing. Lancet Infect Dis, 2011; 11:394–407.
54.
MeehanCJ, HedgeJA, RobertsonDL, et al.: Emergence, dominance, and possible decline of CXCR4 chemokine receptor usage during the course of HIV infection. J Med Virol, 2010; 82:2004–2012.
55.
WangB, MikhailM, DyerWB, et al.: First demonstration of a lack of viral sequence evolution in a nonprogressor, defining replication-incompetent HIV-1 infection. Virology, 2003; 312:135–150.
56.
BelloG, CasadoC, SandonisV, et al.: A subset of human immunodeficiency virus type 1 long-term non-progressors is characterized by the unique presence of ancestral sequences in the viral population. J Gen Virol, 2005; 86:355–364.
57.
BelloG, CasadoC, SandonisV, et al.: Plasma viral load threshold for sustaining intrahost HIV type 1 evolution. AIDS Res Hum Retroviruses, 2007; 23:1242–1250.
58.
BraibantM, AgutH, RouziouxC, et al.: Characteristics of the env genes of HIV type 1 quasispecies in long-term nonprogressors with broadly neutralizing antibodies. J Acquir Immune Defic Syndr, 2008; 47:274–284.
59.
JoosB, TrkolaA, FischerM, et al.: Low human immunodeficiency virus envelope diversity correlates with low in vitro replication capacity and predicts spontaneous control of plasma viremia after treatment interruptions. J Virol, 2005; 79:9026–9037.
60.
MensH, KearneyM, WiegandA, et al.: HIV-1 continues to replicate and evolve in patients with natural control of HIV infection. J Virol, 2010; 84:12971–12981.
61.
JordanMR, KearneyM, PalmerS, et al.: Comparison of standard PCR/cloning to single genome sequencing for analysis of HIV-1 populations. J Virol Methods, 2010; 168:114–120.
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