Cancer Burden in the HIV-Infected Population in the United States

Shiels, Meredith S.; Pfeiffer, Ruth M.; Gail, Mitchell H.; Hall, H. Irene; Li, Jianmin; Chaturvedi, Anil K.; Bhatia, Kishor; Uldrick, Thomas S.; Yarchoan, Robert; Goedert, James J.; Engels, Eric A.

doi:10.1093/jnci/djr076

Cited by 689 publications

(668 citation statements)

References 35 publications

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“…A lthough AIDS-defining cancers have declined following the introduction of combined antiretroviral therapy (cART), non-Hodgkin lymphomas (NHLs) still comprise more than 50% of all AIDS-defining cancers (1) and are the most frequent cause of death in these patients (2). Most HIV-1-related NHLs (HIV-NHLs) are high-grade B-cell lymphomas such as diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL).…”

Section: B-cell Clonogenicitymentioning

confidence: 99%

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

Dolcetti

Giagulli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

102

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Although in decline after successful anti-HIV therapy, B-cell lymphomas are still elevated in HIV-1-seropositive (HIV+) persons, and the mechanisms are obscure. The HIV-1 matrix protein p17 persists in germinal centers long after HIV-1 drug suppression, and some p17 variants (vp17s) activate Akt signaling and promote growth of transformed B cells. Here we show that vp17s derived from four of five non-Hodgkin lymphoma (NHL) tissues from HIV+ subjects display potent B-cell growth-promoting activity. They are characterized by amino acid insertions at position 117-118 (Ala-Ala) or 125-126 (Gly-Asn or Gly-Gln-Ala-Asn-Gln-Asn) among some other mutations throughout the sequence. Identical dominant vp17s are found in both tumor and plasma. Three of seven plasma samples from an independent set of NHL cases manifested multiple Ala insertions at position 117-118, and one with the Ala-Ala profile also promoted B-cell growth and activated Akt signaling. Ultradeep pyrosequencing showed that vp17s with C-terminal insertions are more frequently detected in plasma of HIV+ subjects with than without NHL. Insertion of Ala-Ala at position 117-118 into reference p17 (refp17) was sufficient to confer B-cell growth-promoting activity. In contrast, refp17 bearing the Gly-Asn insertion at position 125-126 did not, suggesting that mutations not restricted to the C terminus can also account for this activity. Biophysical analysis revealed that the Ala-Ala insertion mutant is destabilized compared with refp17, whereas the Gly-Asn form is stabilized. This finding provides an avenue for further exploration of structure function relationships and new treatment strategies in combating HIV-1-related NHL.non-Hodgkin lymphoma | HIV-1 matrix protein p17 | AIDS | p17 variants | B-cell clonogenicity

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Section: B-cell Clonogenicitymentioning

confidence: 99%

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

Dolcetti

Giagulli

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

102

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“…In many cases, malignancies that have arisen in HIV-infected patients are known to be associated with infections by herpes viruses that are normally controlled by the host's immune system (22)(23)(24). However, non-AIDS-defining malignancies have been on the increase since the availability of combination antiretroviral therapy, and the underlying cause of these additional malignancies is poorly understood (25)(26)(27). Although the activation of protooncogenes due to normal HIV-1 integration seems to be extremely rare, which is one of the reasons lentiviral vectors are being tested for gene therapy, there is a report suggesting that HIV integration can cause oncogene activation (28).…”

Section: Discussionmentioning

confidence: 99%

Treatment with suboptimal doses of raltegravir leads to aberrant HIV-1 integrations

Varadarajan

McWilliams

Hughes

2013

Proc. Natl. Acad. Sci. U.S.A.

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Integration of the DNA copy of the HIV-1 genome into a host chromosome is required for viral replication and is thus an important target for antiviral therapy. The HIV-encoded enzyme integrase (IN) catalyzes two essential steps: 3′ processing of the viral DNA ends, followed by the strand transfer reaction, which inserts the viral DNA into host DNA. Raltegravir binds to IN and blocks the integration of the viral DNA. Using the Rous sarcoma virus-derived vector RCAS, we previously showed that mutations that cause one viral DNA end to be defective for IN-mediated integration led to abnormal integrations in which the provirus had one normal and one aberrant end, accompanied by rearrangements in the host genome. On the basis of these results, we expected that suboptimal concentrations of IN inhibitors, which could block one of the ends of viral integration, would lead to similar aberrant integrations. In contrast to the proviruses from untreated cells, which were all normal, ∼10-15% of the proviruses isolated after treatment with a suboptimal dose of raltegravir were aberrant. The aberrant integrations were similar to those seen in the RCAS experiments. Most of the aberrant proviruses had one normal end and one aberrant end and were accompanied by significant rearrangements in the host genome, including duplications, inversions, deletions and, occasionally, acquisition of sequences from other chromosomes. The rearrangements of the host DNA raise concerns that these aberrant integrations might have unintended consequences in HIV-1-infected patients who are not consistent in following a raltegravir-containing treatment regimen.strand transfer inhibitor | chromosomal rearrangements | integrase inhibitors H IV-1 integration is a two-step process: first, in the cytoplasm, an integrase (IN) dimer binds to each end of the newly synthesized linear viral DNA and removes two nucleotides from each of the 3′ ends, exposing the conserved CA dinucleotide. The preintegration complex (PIC) is translocated from the cytoplasm into the nucleus, where the viral DNA is integrated into the host genome. In the strand transfer (ST) reaction, the two exposed 3′ hydroxyl groups on the newly processed viral DNA ends attack phosphodiester bonds on the opposite strands of the target DNA at positions that lie across the major groove, 4-6 bp apart. This reaction is carried out by a tetramer of IN; each of the viral DNA ends is associated with an IN dimer. This transesterification reaction generates an intermediate in which the 3′ ends of the viral DNA are covalently joined to the host DNA and there are 4-to 6-bp gaps in the host DNA associated with both of the 5′ ends of the viral DNA. Cellular machinery repairs these gaps, creating a 4-to 6-bp duplication (the size of the duplication varies for different retroviruses) of the host DNA flanking the integrated viral DNA (1-4). HIV-1 integration generates a 5-bp duplication of the host DNA at the integration site (5, 6).Raltegravir (RAL) and all of the potent IN inhibitors thus far discovered bind to...

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“…Many reasons have been postulated for this including immunodeficiency [1][2][3][4], higher prevalence of traditional cancer risk factors [5], and coinfection by oncogenic viruses, direct pro-oncogenic effects of HIV [6], long-term combination antiretroviral therapy (cART) toxicity [7,8], and activated inflammation and coagulation [9,10]. Because of this inherent increased risk and given the fact that HIV-infected persons are now living much longer [11], cancer has emerged as a major cause of morbidity and death in the cART era [12].…”

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confidence: 99%

Immediate Antiretroviral Therapy Reduces Risk of Infection-Related Cancer During Early HIV Infection

et al. 2016

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Background. In the Strategic Timing of Antiretroviral Treatment (START) study, immediate combination antiretroviral therapy (cART) initiation reduced cancer risk by 64%. We hypothesized that risk reduction was higher for infection-related cancer and determined by differences in CD4 cell counts and human immunodeficiency virus (HIV) RNA between the study arms.Methods. Incident malignancies in START were categorized into infection-related and infection-unrelated cancer. We used Cox models to assess factors associated with both cancer categories. We used sequential adjustment for baseline covariates, cancer risk factors, and HIV-specific variables to investigate potential mediators of cancer risk reduction with immediate cART.Results. There were 14 cancers among persons randomized to immediate cART (6 infection-related and 8 infection-unrelated) and 39 cancers in the deferred arm (23 infection-related and 16 infection-unrelated); hazard ratios of immediate vs deferred cART initiation were 0.26 (95% confidence interval [CI], .11-.64) for infection-related and 0.49 (95% CI, .21-1.15) for infection-unrelated cancer. Independent predictors of infection-related cancer were older age, higher body mass index, low-to middle-income region, HIV RNA, and baseline CD8 cell count. Older age and baseline CD8 cell count were independent predictors of infection-unrelated cancer. Adjustment for latest HIV RNA level had little impact on the protective effect of immediate cART on infection-related cancer. Adjustment for latest HIV RNA level, but not for CD4 cell count or cancer risk factors, attenuated the effect of immediate cART on infection-unrelated cancer.Conclusions. Immediate cART initiation significantly reduces risk of cancer. Although limited by small sample size, this benefit does not appear to be solely attributable to HIV RNA suppression and may be also mediated by other mechanisms.

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Cancer Burden in the HIV-Infected Population in the United States

Abstract: Over a 15-year period (1991-2005), increases in non-AIDS-defining cancers were mainly driven by growth and aging of the AIDS population. This growing burden requires targeted cancer prevention and treatment strategies.

Cited by 689 publications

References 35 publications

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

Role of HIV-1 matrix protein p17 variants in lymphoma pathogenesis

Treatment with suboptimal doses of raltegravir leads to aberrant HIV-1 integrations

Immediate Antiretroviral Therapy Reduces Risk of Infection-Related Cancer During Early HIV Infection

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