An HIV-infected patient presenting an unexpected viral escape under combined antiretroviral treatment is described. The virus isolated from plasma contained a large deletion in the HIV-1 integrase gene but no known resistance mutation. Nested polymerase chain reactions (PCRs) with patient virus integrase-specific primers and probes were developed and used to detect the mutant from plasma, blood, rectal biopsies, and sperm. The variant progressively emerged during a period of therapy-induced virosuppression, and persisted at a low but detectable level for at least 5 years. Surprisingly, proviral DNA from lymphocytes, rectal cells, and sperm cells was, and remained, mainly wild type. Cellular HIV RNA with the deletion was detected only once from the rectum. The origin and mechanisms underlying this so far not described production at a detectable level are largely hypothetical. This observation raised concern about the ability of defective viruses to spread.
Get full access to this article
View all access options for this article.
References
1.
CoffinJM: HIV population dynamics in vivo: Implications for genetic variation, pathogenesis, and therapy. Science, 1995; 267:483–489.
2.
SanchezG, XuX, ChermannJC, and HirschI: Accumulation of defective viral genomes in peripheral blood mononuclear cells of human immunodeficiency virus type 1-infected individuals. J Virol, 1997; 71:2233–2240.
3.
HoYC, ShanL, HosmaneNN, et al.: Replication competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell, 2013; 155:540–551.
4.
ChomontN, El-FarM, AncutaP, et al.: HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med, 2009; 15:893–900.
5.
DahlV, JosefssonL, and PalmerS: HIV reservoirs, latency, and reactivation: prospects for eradication. Antiviral Res, 2010; 85:286–294.
6.
PaceMJ, AgostoL, GrafEH, and O'DohertyU: HIV reservoirs and latency models. Virology, 2011; 411:344–354.
7.
JenkinsTM, EngelmanA, GhirlandoR, and CraigieR: A soluble active mutant of HIV-1 integrase: Involvement of both the core and carboxyl-terminal domains in multimerization. J Biol Chem, 1996; 271:7712–7718.
8.
DolanJ, ChenA, WeberIT, HarrisonRW, and LeisJ: Defining the DNA substrate binding sites on HIV-1 integrase. J Mol Biol, 2009; 385:568–579
9.
CellierC, MoreauK, GallayK, BallandrasA, GouetP, and RonfortC: In vitro functional analyses of the human immunodeficiency virus type 1 (HIV-1) integrase mutants give new insights into the intasome assembly. Virology, 2013; 439:97–104.
10.
SaisonJ, FerryT, DemaretJ, et al.: Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients. Clin Exp Immunol, 2014; 176:401–409.
11.
EngelmanA: Reverse transcription and integration. In: Retroviruses: Molecular Biology Genomics and Pathogenesis (KurthR, BannertN, eds.). Caister Academic Press, Norfolk, UK, 2010, pp. 129–159.
12.
KrishnanL, LiX, NaraharisettyHL, HareS, CherepanovP, and EngelmanA: Structure-based modeling of the functional HIV-1 intasome and its inhibition. Proc Natl Acad Sci USA, 2010; 107:15910–15915.
13.
MowatAM: Anatomical basis of tolerance and immunity to intestinal antigens. Nat Rev Immunol, 2003; 3:331–341.
14.
LingB, MohanM, LacknerAA, et al.: The large intestine as a major reservoir for simian immunodeficiency virus in macaques with long-term, nonprogressing infection. J Infect Dis, 2010; 202:1846–1854.
15.
Van MarleG, GillMJ, KolodkaD, McManusL, GrantT, and ChurchDL: Compartmentalization of the gut viral reservoir in HIV-1 infected patients. Retrovirology, 2007; 4:87.
16.
YuklSA, ShergillAK, McQuaidK, et al.: Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS, 2010; 24:2451–2460.
17.
BuzónMJ, MassanellaM, Libre, et al.: HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med, 2010; 16:460–465.
18.
ChunT-W, MurrayD, JustementJS, et al.: Relationship between residual plasma viremia and the size of HIV proviral DNA reservoirs in infected individuals receiving effective antiretroviral therapy. J Infect Dis, 2011; 204:135–138.
19.
PolesMA, BoscardinWJ, ElliottJ, et al.: Lack of decay of HIV-1 in gut-associated lymphoid tissue reservoirs in maximally suppressed individuals. J Acquir Immune Defic Syndr, 2006; 43:65–68.
20.
EveringTH, MehandruS, RaczP, et al.: Absence of HIV-1 evolution in the gut-associated lymphoid tissue from patients on combination antiviral therapy initiated during primary infection. PLoS Pathog, 2012; 8:e1002506.
21.
BaileyJR, SedaghatAR, KiefferT, et al.: Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells. J Virol, 2006; 80:6441–6457.
22.
BrennanTP, WoodsJO, SedaghatAR, SilicianoJD, SilicianoRF, and WilkeCO: Analysis of human immunodeficiency virus type 1 viremia and provirus in resting CD4+ T cells reveals a novel source of residual viremia in patients on antiretroviral therapy. J Virol, 2009; 83:8470–8481.
23.
JosefsonL, von StokenstromS, FariaNR, et al.: The HIV reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time. Proc Natl Acad Sci USA, 2013; 110:E4987–4996.
24.
MaldarelliF, WuX, KearneyM, et al.: The role of HIV integration sites in extensive clonal expansion of infected cells in patients. Top Antivir Med, 2014; 22(e-1):193.
25.
WagnerTA, McLaughlinS, GargK, et al.: Proliferation of cells with HIV integrated into regulatory genes is a mechanism of persistence. Top Antivir Med, 2014; 22(e-1):69.
26.
TriniteB, OhlsonEC, VoznescenskyI, et al.: An HIV-1 replication pathway utilizing reverse transcription products that fail to integrate. J Virol, 2013; 87:12701–12720.
27.
PaolucciS, FoliA, GulminettiR, et al.: HIV-1 plasma variants encoding truncated reverse transcriptase (RT) in a patient with high RT-specific CD8+ memory T-cell response. Curr HIV Res, 2009; 7:302–310.
28.
PaolucciS, GulminettiR, MaseratiR, DossenaL, and BaldantiF: Accumulation of defective HIV-1 variants in a patient with slow disease progression. Curr HIV Res, 2011; 9:17–22.
29.
BrockmanMA, ChoperaDR, OlveraA, et al.: Uncommon pathways of immune escape attenuate HIV-1 integrase replication capacity. J Virol, 2012; 86:6913–6923.
PoeschlaE: The importance of becoming double-stranded: Innate immunity and the kinetic model of HIV-1 central plus strand synthesis. Virology, 2013; 441:1–11.
32.
GirodA, DryndaA, CossetFL, VerdierG, and RonfortC: Homologous and nonhomologous retroviral recombinations are both involved in the transfer by infectious particles of defective avian leukosis virus-derived transcomplementing genomes. J Virol, 1996; 70:5651–5657.
33.
LapriseC, de PokomandyA, BarilJ-G, DufresneS, and TrottierH: Virologic failure following persistent low-level viremia in a cohort of HIV-positive patients: Results from 12 years of observation. Clin Infect Dis, 2013; 57:1489–1496.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
