Archive for July 29, 2016

Persistent HIV-1 replication during antiretroviral therapy

Current Opinion In HIV and AIDS July 2016 V.11 N.4 P.417–423

Martinez-Picado, Javier; Deeks, Steven G

aAIDS Research Institute IrsiCaixa, Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona, Badalona

bUniversity of Vic-Central University of Catalonia (UVic-UCC), Vic

cInstitució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

dDepartment of Medicine, University of California, San Francisco, California, USA

Purpose of review

The present review will highlight some of the recent findings regarding the capacity of HIV-1 to replicate during antiretroviral therapy (ART).

Recent findings

Although ART is highly effective at inhibiting HIV replication, it is not curative. Several mechanisms contribute to HIV persistence during ART, including HIV latency, immune dysfunction, and perhaps persistent low-level spread of the virus to uninfected cells (replication). The success in curing HIV will depend on efficiently targeting these three aspects. The degree to which HIV replicates during ART remains controversial. Most studies have failed to find any evidence of HIV evolution in blood, even with samples collected over many years, although a recent very intensive study of three individuals suggested that the virus population does shift, at least during the first few months of therapy. Stronger but still not definitive evidence for replication comes from a series of studies in which standard regimens were intensified with an integration inhibitor, resulting in changes in episomal DNA (blood) and cell-associated RNA (tissue). Limited drug penetration within tissues and the presence of immune sanctuaries have been argued as potential mechanisms allowing HIV to spread during ART. Mathematical models suggest that HIV replication and evolution is possible even without the selection of fully drug-resistant variants. As persistent HIV replication could have clinical consequences and might limit the efficacy of curative interventions, determining if HIV replicates during ART and why, should remain a key focus of the HIV research community.


Residual viral replication likely persists in lymphoid tissues, at least in a subset of individuals. Abnormal levels of immune activation might contribute to sustain virus replication.




July 29, 2016 at 7:17 pm

Strategies to target HIV-1 in the central nervous system

Current Opinion In HIV and AIDS July 2016 V.11 N.4

Gray, Lachlan R.; Brew, Bruce J.; Churchill, Melissa J.

Strategies to target HIV-1 in the central nervous system

Gray, Lachlan R.; Brew, Bruce J.; Churchill, Melissa J.

aCenter for Biomedical Research, Burnet Institute

bDepartment of Infectious Diseases, Monash University, Melbourne, Victoria

cDepartments of Neurology, Immunology and Infectious Diseases and Peter Duncan Neurosciences Unit, St Vincent’s Centre for Applied Medical Research, St Vincent’s Hospital, Sydney, New South Wales

dDepartment of Microbiology, Monash University, Clayton, Victoria

eDepartment of Medicine, Monash University, Melbourne, Victoria, Australia

Purpose of review

To review current knowledge of viral reservoirs in the central nervous system (CNS) and identify the CNS-specific barriers and strategies to cure human immunodeficiency virus type 1 (HIV-1) within the brain.

Recent findings

The cumulative data of HIV-1 infection of the CNS support the ability of the CNS to act as a viral reservoir for HIV-1. The HIV-1 viral strains found in the CNS are distinct to those found in other parts of the body. These differences have been well documented for env and also extend to the viral promoter, the long terminal repeat, and influence the ability of the virus to replicate, establish latency and respond to latency-reversing agents (LRAs). In addition, the bioavailability and activity of LRAs and antiretrovirals within the CNS suggest altered properties compared with the blood, which may influence their effectiveness. Selected LRAs were shown to have reduced effectiveness against CNS-derived viral strains compared with blood-derived strains from the same patients. Finally, altered immune surveillance within the CNS may also interfere with the efficiency of cure strategies within this compartment.


Together, these data suggest that the CNS viral reservoir is unique and presents a distinct set of challenges that need to be overcome to ensure successful viral elimination within this compartment. Future studies will need to develop CNS-active LRAs and biomarkers to enable monitoring and evaluation of treatment outcomes within the CNS during HIV-1 cure clinical trials.



July 29, 2016 at 7:15 pm

Surviving Severe Sepsis: Is That Enough?

Critical Care Medicine August 2016 V.44 N.8 P.1603–1604


Anderson-Shaw, Lisa

Department of Clinical Ethics Consult Service, UI Health, University of Illinois at Chicago, Chicago, IL

Sepsis and severe forms of sepsis is a frequent diagnosis in the ICU setting. “Sepsis is one of the oldest and most elusive syndromes in medicine” (1). The definition of severe sepsis includes a systemic inflammatory response to infection complicated by acute organ dysfunction (1). “Over 1,665,000 cases of sepsis occur in the United States each year, with a mortality rate up to 50%” (2). In the ICU setting survival of severe sepsis is a primary goal, however, quality-of-life (QoL) issues for these patients after discharge is of great concern to the patient and to their family and physicians who will be providing the follow-up care that may be complex and ongoing (3). Long after hospitalization, survivors of severe sepsis experience an impaired QoL and an ongoing feeling that they may be imposing a burden of care to their family and loved ones. This is especially true for survivors who where physically independent prior to severe sepsis, but after discharge are left with dependence on others in daily activities. Although the goal of care in the ICU setting is appropriately to cure sepsis and minimize morbidity, it may be that many survivors are not getting the ongoing care required for their complex physical, psychological, and emotional needs after discharge. A recent study reported that after 6 months, up to 80% of severe sepsis/septic shock survivors stopped coming to their follow-up consultations (4). It is important to study QoL for survivors of sepsis in order to provide patient-centered care and to assess goals of care frequently so survivors and their families are offered holistic care and are not lost to follow-up…..



July 29, 2016 at 2:30 pm

Sepsis-3: What is the Meaning of a Definition?

Critical Care Medicine August 2016 V.44 N.8 P.1459–1460

Marshall, John C.

Departments of Surgery and Critical Care Medicine, Keenan Research Centre for Biomedical Science of the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada

The recent publication of Sepsis-3–the latest iteration of an effort to define sepsis–has evoked an impressive response (1). To date it has been viewed more than one million times on the JAMA website, making it one of the most highly accessed articles there in recent years. It has also generated a flurry of commentaries–some supportive, some opposing, and almost all thoughtful (2–4). Indeed recognizing as the original paper did that the new definition is simply the next step in the evolution of a challenging process, the controversy is as important as the Sepsis-3 document in clarifying what has been accomplished and what remains undone.According to the Merriam-Webster Dictionary, a definition is “…an explanation of the meaning of a word…”. Sepsis to the Greeks denoted a range of processes characterized by putrefaction and a foul smell (5). With the identification of the pathogenic role of microorganisms in disease, sepsis has come to take on a meaning related to the consequences of infection. This meaning has changed as our understanding of the biology of infection and the host response has evolved. In the early 1970s, Stedman’s Medical Dictionary defined sepsis as “…the presence of pus-forming organisms in the bloodstream…”, however this definition rapidly became obsolete with the discovery that the adverse sequelae of infection arose through the activation of a host response, rather than as a consequence of the intrinsic toxicity of the microorganism or its products. A new definition was needed. In 1991, a consensus conference of the SCCM and ACCP suggested that sepsis is “…the systemic host response to invasive infection …” (6). Further cognizant of the fact that an identical clinical response could be evoked by non-infectious stimuli, they proposed a neologism, the systemic inflammatory response syndrome (SIRS), to denote the response independent of its cause. Time and reflection rendered this definition inadequate…..



July 29, 2016 at 2:29 pm


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