INSIGHTS | PERSPECTIVES
in the seas
Concern is rising about
of the marine environment
OCEANS encode products involved in controlling the
cell division cycle or cancer progression. This
supports the hypothesis that disruption of
these genes by proviral insertion promotes
growth or persistence of the host cell (13).
Maldarelli et al. and Wagner et al. identify
the host gene encoding the basic leucine
zipper transcription factor 2 (BACH2) as a
frequent site of HIV integration. BACH2 is a
transcriptional regulator that controls CD4+
T cell senescence and cytokine homeostasis
(14). Thus, the new findings suggest a link
between the persistence of latently infected
cells and proviral integration in genes related
to cell proliferation and cancer.
Further experiments should strengthen
these ideas. There is as yet no molecular evidence that such integrations of HIV-1 lead directly to the proliferation of latently infected
cells, but it should be possible to engineer
viral integration into specific sites of the host
cell genome and demonstrate cell proliferation. In addition, there is as yet no proof that
the proviruses encode for replication-competent HIV genomes. Maldarelli et al. did carry
out the Herculean task of single-genome amplification and sequencing tiny amounts of
HIV RNA recovered from the plasma of some
patients studied. This verified a close similarity of circulating viral envelope sequences to
those found in integrated proviral genomes
in expanded clones. However, like prior studies (11), such sequencing is limited to a small
portion of the HIV genome, and cannot eliminate the possibility of inactivating mutations
in other parts of the proviral genome, making the virus incompetent to replicate. Given
that the cells harboring quiescent HIV-1
are only a tiny minority of the total CD4+ T
cell population examined by Maldarelli et
al. or Wagner et al., and that years of ART
have allowed for years of selection, alternative interpretations of the data are possible.
For example, it is not yet ruled out that the
expanded T cell clones detected could be expanding for other reasons (e.g., in response
to stimulation by a specific antigen). There
may be other reasons for preferential viral
integration into the genes described as well.
There may also be “survivor bias” in the detection of replication-incompetent genomes.
Indeed, given the model, it is puzzling that
no increase in the total number of HIV DNA-
positive cells was observed.
The findings of Maldarelli et al. and Wagner et al. raise additional issues. Lentiviral
vectors are used extensively in therapeutic gene transfer, so monitoring for related
events of proliferation-promoting integration with these vectors during gene therapy
is important. Indeed, clonal expansion was
observed in the case of a lentiviral-based
gene correction of the blood disorder beta-thalassemia in which integration at the site
of a proto-oncogene increased cell proliferation (15). In this case, the host gene encoding high-mobility group AT-hook 2 (HMGA2)
produced a truncated mRNA due to vector insertion within the gene. HMGA2 is a
transcription regulatory protein. The truncated mRNA removed a binding site for a
microRNA that negatively controls HMGA2
expression. The result was increased accumulation of HMG2A mRNA and protein.
HMGA2 was not an integration target in the
cells studied by Maldarelli et al. or Wagner
et al., raising questions about the differences
between latent HIV infections and beta-thal-assemia gene therapy.
Both studies also mention the concern
that HIV integration could contribute to the
development of cancers by insertional mu-tagenesis. However most HIV-related malignancies are not T cell cancers, and even most
HIV-related lymphomas are of B cell origin.
HIV cancers are not thought to harbor integrated HIV DNA, although this could be
If blocking proliferation of latently infected
cells proves to be necessary, it will complicate
efforts to clear the latent reservoir. But clearance of this reservoir is crucial to achieve a
cure of HIV infection. ■
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2. T. Wagner et al., Science; 10.1126/science.1256304 (2014).
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“… findings suggest a link
By Kara Lavender Law1 and
between the persistence
of latently infected cells
and proviral integration
in genes related to cell
Richard C. Thompson2
Plastic debris in the marine environ- ment is more than just an unsightly problem. Images of beach litter and large floating debris may first come to mind, but much recent concern about plastic pollution has focused
on microplastic particles too small to be
easily detected by eye (see the figure). Microplastics are likely the most numerically
abundant items of plastic debris in the
ocean today, and quantities will inevitably
increase, in part because large, single plastic items ultimately degrade into millions
of microplastic pieces. Microplastics are
of environmental concern because their
size (millimeters or smaller) renders them
accessible to a wide range of organisms at
least as small as zooplankton, with potential for physical and toxicological harm.
Since its introduction in the published
literature in 2004 (1), the term microplastic has been widely used to describe plastic fragments in the marine environment.
Typically considered to be smaller than 5
mm in diameter, microplastics are ill defined by size, with ranges that vary between studies. In most open-water studies,
microplastics are measured with plankton
nets, and particles smaller than the net
mesh (typically ~0.33 mm) can evade capture. In marine sediment, bulk sampling
can retain particles of all sizes; however,
efficient identification is a serious challenge in quantifying microplastic loads,
especially with decreasing size. Spectroscopic analysis has identified individual
fragments of common plastics as small as
20 µm in diameter.
The sources of microplastic include fragmentation of larger items entering by rivers, runoff, tides, winds, and catastrophic
events, together with at-sea sources, including lost cargo and fishing and aquaculture
gear. There are also direct inputs of microplastics as micrometer-sized particles,
such as cosmetic beads and clothing fibers
1Departments of Medicine, Microbiology and Immunology,
and Epidemiology, University of North Carolina at Chapel
Hill, 120 Mason Farm Road, Chapel Hill, NC 27599–7042,
USA. 2Perelman School of Medicine, 3610 Hamilton Walk,
Philadelphia, PA 19104, USA. E-mail: email@example.com;