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. 2015 Aug 15;212(4):596-607.
doi: 10.1093/infdis/jiv092. Epub 2015 Feb 23.

Longitudinal Genetic Characterization Reveals That Cell Proliferation Maintains a Persistent HIV Type 1 DNA Pool During Effective HIV Therapy

Susanne von Stockenstrom  1 , Lina Odevall  2 , Eunok Lee  3 , Elizabeth Sinclair  4 , Peter Bacchetti  5 , Maudi Killian  4 , Lorrie Epling  4 , Wei Shao  6 , Rebecca Hoh  4 , Terence Ho  4 , Nuno R Faria  7 , Philippe Lemey  7 , Jan Albert  1 , Peter Hunt  4 , Lisa Loeb  4 , Christopher Pilcher  4 , Lauren Poole  4 , Hiroyu Hatano  4 , Ma Somsouk  4 , Daniel Douek  8 , Eli Boritz  8 , Steven G Deeks  4 , Frederick M Hecht  4 , Sarah Palmer  9
Affiliations

Longitudinal Genetic Characterization Reveals That Cell Proliferation Maintains a Persistent HIV Type 1 DNA Pool During Effective HIV Therapy

Susanne von Stockenstrom et al. J Infect Dis. .

Abstract

Background: The stability of the human immunodeficiency virus type 1 (HIV-1) reservoir and the contribution of cellular proliferation to the maintenance of the reservoir during treatment are uncertain. Therefore, we conducted a longitudinal analysis of HIV-1 in T-cell subsets in different tissue compartments from subjects receiving effective antiretroviral therapy (ART).

Methods: Using single-proviral sequencing, we isolated intracellular HIV-1 genomes derived from defined subsets of CD4(+) T cells from peripheral blood, gut-associated lymphoid tissue and lymph node tissue specimens from 8 subjects with virologic suppression during long-term ART at 2 time points (time points 1 and 2) separated by 7-9 months.

Results: DNA integrant frequencies were stable over time (<4-fold difference) and highest in memory T cells. Phylogenetic analyses showed that subjects treated during chronic infection contained viral populations with up to 73% identical sequence expansions, only 3 of which were observed in specimens obtained before therapy. At time points 1 and 2, such clonally expanded populations were found predominantly in effector memory T cells from peripheral blood and lymph node tissue specimens.

Conclusions: Memory T cells maintained a relatively constant HIV-1 DNA integrant pool that was genetically stable during long-term effective ART. These integrants appear to be maintained by cellular proliferation and longevity of infected cells, rather than by ongoing viral replication.

Keywords: HIV-1 persistence; HIV-1 reservoir; memory T cells.

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Figures

Figure 1.
Figure 1.
Phylogenetic analysis of viral sequences (gag-pol) from plasma specimens isolated before the initiation of antiretroviral therapy and cells isolated from time points 1 and 2. Maximum likelihood trees of sequences (gag-pol) from plasma specimens isolated 1.5 years before initiation of therapy, plasma specimens isolated just before initiation of therapy, plasma specimens obtained during therapy, intracellular sequences isolated at time point 1, and intracellular sequences isolated at time point 2 from a subset of subjects initiating antiviral therapy during acute/early human immunodeficiency virus type 1 (HIV-1) infection (subject 4 [A] and subject 5 [B]) and during chronic HIV-1 infection (subject 7 [C] and subject 8 [D]). Trees representing the sequences isolated from subjects 1, 2, 3, and 6 are not shown but are available upon request.
Figure 2.
Figure 2.
Phylogenetic analysis of viral sequences (env) from plasma specimens isolated before the initiation of antiretroviral therapy and cells isolated at time points 1 and 2. Maximum likelihood trees of sequences (env) from plasma specimens isolated 1.5 years before initiation of therapy, plasma specimens isolated just before initiation of therapy, intracellular sequences isolated at time point 1, and intracellular sequences isolated at time point 2 from a subset of subjects initiating antiviral therapy during acute/early human immunodeficiency virus type 1 (HIV-1) infection (subject 5; A) and during chronic HIV-1 infection (subject 7 [B] and subject 8 [C]).
Figure 3.
Figure 3.
Phylogenetic analysis of identical viral sequences (gag-pol) from plasma specimens isolated before the initiation of antiretroviral therapy, plasma specimens obtained during therapy and cells isolated from time points 1 and 2 after several years of suppressive antiretroviral therapy. Maximum likelihood trees of sequences (gag-pol) from plasma specimens (isolated 1.5 years before initiation of therapy, just before initiation of therapy, and during therapy), peripheral blood specimens (all memory T cells, central/transitional memory T cells, central memory T cells, transitional memory T cells, and effector memory T cells), gut-associated lymphoid tissue (GALT) specimens (naive T cells, central/transitional memory T cells, and effector memory T cells), and lymph node tissue specimens (naive T cells, central memory T cells, transitional memory T cells, and effector memory T cells) from a subset of subjects initiating antiviral therapy during chronic human immunodeficiency virus type 1 infection (subject 6 [A], subject 7 [B], and subject 8 [C]). Red circles indicate identical sequences expansions (defined as ≥2 genetically identical sequences) isolated from different cells. Arrows indicate identical sequence expansions, which included sequences derived from plasma specimens obtained before therapy.
Figure 4.
Figure 4.
Phylogenetic analysis of identical viral sequences (env) from plasma specimens isolated before the initiation of antiretroviral therapy and cells isolated from time points 1 and 2 after several years of suppressive antiretroviral therapy. Maximum likelihood trees of sequences (env) from plasma specimens (isolated 1.5 years before initiation of therapy and just before initiation of therapy), peripheral blood specimens (naive T cells, all memory T cells, central/transitional memory T cells, central memory T cells, transitional memory T cells, and effector memory T cells), gut-associated lymphoid tissue (GALT) specimens (naive T cells, central/transitional memory T cells, and effector memory T cells), and lymph node tissue specimens from time point 2 (naive T cells, central memory T cells, transitional memory T cells, and effector memory T cells) from a subset of subjects initiating antiviral therapy during chronic human immunodeficiency virus type 1 infection (subject 7 [A] and subject 8 [B]). Red circles indicate identical sequences expansions (defined as ≥2 genetically identical sequences) isolated from different cells. Arrows indicate identical sequence expansions, which included sequences derived from specimens obtained before therapy.
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