Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection

Mathematical modeling of viral replication dynamics, based on sequential measurements of levels of virion-associated RNA in plasma during antiretroviral treatment, has led to fundamental new insights into human immunodeficiency virus type 1 pathogenesis. We took advantage of the simian immunodeficiency virus (SIV)-infected macaque model to perform detailed measurements and mathematical modeling during primary infection and during treatment of established infection with the antiretroviral drug (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA). The calculated clearance half-life for productively infected cells during resolution of the peak viremia of primary infection was on the order of 1 day, with slightly shorter clearance half-lives calculated during PMPA treatment. Viral reproduction rates upon discontinuation of PMPA treatment after 2 weeks were approximately twofold greater than those obtained just prior to initiation of treatment in the same animals, likely reflecting accumulation of susceptible target cells during treatment. The basic reproductive ratio (R0) for the spread of SIV infection in vivo, which represents the number of productively infected cells derived from each productively infected cell at the beginning of infection, was also estimated. This parameter quantifies the extent to which antiviral therapy or vaccination must limit the initial spread of virus to prevent establishment of chronic disseminated infection. The results thus provide an important guide for efforts to develop vaccines against SIV and, by extension, human immunodeficiency virus.     

External and internal electrostatic potentials of cholinesterase models

The electrostatic potentials for the three-dimensional structures of cholinesterases from various species were calculated, using the Delphi algorithm, on the basis of the Poisson–Boltzmann equation. We used structures for Torpedo californica and mouse acetylcholinesterase, and built homology models of the human, Bungarus fasciatus, and Drosophila melanogaster acetylcholinesterases and human butyrylcholinesterase. All these structures reveal a negative external surface potential, in the area around the entrance to the active-site gorge, that becomes more negative as the rim of the gorge is approached. Moreover, in all cases, the potential becomes increasingly more negative along the central axis running down the gorge, and is largest at the base of the gorge, near the active site. Ten key acidic residues conserved in the sequence alignments of AChE from various species, both in the surface area near the entrance of the active-site gorge and at its base, appear to be primarily responsible for these potentials. The potentials are highly correlated among the structures examined, down to sequence identities as low as 35%. This indicates that they are a conserved property of the cholinesterase family, could serve to attract the positively charged substrate into and down the gorge to the active site, and may play other roles important for cholinesterase function.     

Mechanism of production of intestinal secretion by negative luminal pressure

The relationships between luminal hydrostatic pressure and fluid transport by dog jejunum in vivo studied as a sheet in the Wells clamp were compared with quantitative predictions from a model proposed for the mechanism of the secretion produced by elevated venous pressure. According to the model, the secretion produced by increasing venous pressure and the secretion produced by negative luminal pressure are both passive filtrates contingent on a transepithelial pressure of a few centimeters of H2O. We consider that the agreement between the observed and predicted responses to luminal pressure provides strong support for the model. In particular, a) the observations displayed a predicted gross asymmetry in rates of fluid transfer with isotonic fluids depending on whether the luminal pressure was positive or negative; b) the observed magnitude of the negative luminal pressure required for the onset of secretion agreed with predictions; and c) the secretion contained significant amounts of protein at about 25% of the plasma concentration.     

High-risk sexual behavior and knowledge of HIV antibody status in the San Francisco City Clinic Cohort.

Evaluated the effectiveness of human immunodeficiency virus (HIV) testing and counseling among homosexual and bisexual men participating in the San Francisco City Clinic Cohort (Centers for Disease Control, 1987). Behavioral data from 181 men who learned their HIV antibody status between 1985 and 1987 were compared with data from 128 men who were tested but declined to receive their results. Significant declines in risk indices for unprotected receptive and insertive anal intercourse occurred between 1983–1984 and 1986–1987, but these declines were independent of both knowledge of HIV status and actual serostatus. Ss who chose to learn their HIV status were no more likely to report depression or anxiety subsequent to testing. Frequent access to and discussion of risk-reduction information may be important motivators of behavioral change. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Vpx is required for dissemination and pathogenesis of SIV(SM) PBj: evidence of macrophage-dependent viral amplification

The viral accessory protein Vpx is required for productive in vitro infection of macrophages by simian immunodeficiency virus from sooty mangabey monkeys (SIV(SM)). To evaluate the roles of Vpx and macrophage infection in vivo, we inoculated pigtailed macaques intravenously or intrarectally with the molecularly cloned, macrophage tropic, acutely pathogenic virus SIV(SM) PBj 6.6, or accessory gene deletion mutants (deltaVpr or deltaVpx) of this virus. Both wild-type and SIV(SM) PBj deltaVpx viruses were readily transmitted across the rectal mucosa. A subsequent 'stepwise' process of local amplification of infection and dissemination was observed for wild-type virus, but not for SIV(SM) PBj deltaVpx, which also showed considerable impairment of the overall kinetics and extent of its replication. In animals co-inoculated with equivalent amounts of wild-type and SIV(SM) Pbj deltaVpx intravenously or intrarectally, the deltaVpx mutant was at a strong competitive disadvantage. Vpx-dependent viral amplification at local sites of initial infection, perhaps through a macrophage-dependent mechanism, may be a prerequisite for efficient dissemination of infection and pathogenic consequences after exposure through either mucosal or intravenous routes.     

Patterns of viral replication correlate with outcome in simian immunodeficiency virus (SIV)-infected macaques: effect of prior immunization with a trivalent SIV vaccine in modified vaccinia virus Ankara

The dynamics of plasma viremia were explored in a group of 12 simian immunodeficiency virus (SIV)-infected rhesus macaques (Macaca mulatta) that had received prior immunization with either nonrecombinant or trivalent (gag-pol, env) SIV-recombinant vaccinia viruses. Three distinct patterns of viral replication observed during and following primary viremia accounted for significant differences in survival times. High-level primary plasma viremia with subsequently increasing viremia was associated with rapid progression to AIDS (n = 2). A high-level primary plasma virus load with a transient decline and subsequent progressive increase in viremia in the post-acute phase of infection was associated with progression to AIDS within a year (n = 6). Low levels of primary plasma viremia followed by sustained restriction of virus replication were associated with maintenance of normal lymphocyte subsets and intact lymphoid architecture (n = 4), reminiscent of the profile observed in human immunodeficiency virus type 1-infected long-term nonprogressors. Three of four macaques that showed this pattern had been immunized with an SIV recombinant derived from the attenuated vaccinia virus, modified vaccinia virus Ankara. These data link the dynamics and extent of virus replication to disease course and suggest that sustained suppression of virus promotes long-term, asymptomatic survival of SIV-infected macaques. These findings also suggest that vaccine modulation of host immunity may have profound beneficial effects on the subsequent disease course, even if sterilizing immunity is not achieved.     

Concordance of PCR and antibody results from HIV testing of injecting drug users

Standard HIV-1 testing relies on the enzyme immunoassay (EIA) for detecting antibodies specific to HIV-1. This technique may misclassify persons as HIV-1-negative in instances where testing follows infection but precedes development of antibody to HIV-1. To evaluate the occurrence of HIV infection in the absence of positive antibody, polymerase chain reaction (PCR) for viral DNA in the blood has been applied. Research comparing these two testing techniques has generally focused on populations of homosexual and bisexual men. This study compares PCR and antibody testing of 337 injecting drug users recruited from street settings in San Francisco. Of 286 HIV-1 antibody-negative samples, 3 (1.0%) were PCR-positive. Of 49 HIV-1 antibody-positive samples, 1 (2.0%) was PCR-negative. Two samples were antibody-indeterminate and PCR-negative. This yielded an overall concordance of 331/335 (98.8%), excluding the indeterminate results. These results suggest that current antibody methodology is adequate. However, misclassification among recently infected individuals may occur, which is of concern in high-incidence groups.     

Mechanism of production of intestinal secretion by elevated venous pressure

A study was carried out to elucidate the physiological mechanisms responsible for the intestinal secretion produced by venous pressure elevation. In dogs, measurements were made of the rate and composition of small intestinal secretion, rate of flow and composition of intestinal lymph, plasma composition, and mucosal water content, all in response to elevations of intestinal venous pressure. Venous pressure elevations above a threshold value of 30-35 cm H2O produce secretion at a rate of approximately proportional to the value of the pressure minus the threshold value. Above the threshold value, there were large increases in the rates of lymph flow and net sustained transcapillary filtration. These rates were also roughly proportional to the incremental venous pressure. It is concluded that intestinal secretion produced by elevated venous pressure is almost surely secretory filtration, a passive process with the driving force for secretion an increase in mucosal tissue fluid pressures to values of only some 4-6 cm H2O. The increased tissue fluid pressure not only provides the driving force but also produces an increase in the hydraulic permeability of the epithelium without which the driving force would be ineffective. The transepithelial channels are large enough to permit insulin to pass freely and even plasma protein to pass in large amounts, and hence are most probably intercellular. Secretory filtration probably represents a general pathophysiological response of transporting epithelia to elevated tissue fluid pressure. It is proposed that the threshold value for secretion and associated changes is explained by dilution of the tissue fluid protein colloid osmotic pressure in a small subepithelial, juxtacapillary compartment.     

Role and long-term results of laparoscopic decortication in solitary cystic and autosomal dominant polycystic kidney disease

PURPOSE: Access to retroperitoneal structures via the laparoscope has become established for various conditions. This minimally invasive approach has distinct advantages over conventional open surgery. We document our experience with laparoscopic cyst decortication for diseases of the kidney, including simple and complex cysts, multiple cysts and autosomal dominant polycystic kidney disease. MATERIALS AND METHODS: We retrospectively reviewed the records of 17 patients who underwent a total of 20 procedures. Cases were categorized as polycystic kidney disease and nonpolycystic kidney disease. Factors analyzed were estimated blood loss, length of surgical procedure, hospital stay and complications. Followup included radiographic studies (computerized tomography and/or renal sonography) and patient subjective pain relief, as determined by clinical records and telephone interview. RESULTS: Nine and 11 procedures were done for nonpolycystic kidney disease and polycystic kidney disease, respectively. Of the 8 patients with polycystic kidney disease 3 underwent repeat procedures. Followup was 3 to 63 months (average 26). All patients with simple cysts who were treated for pain were pain-free at the latest followup. Of the 10 procedures 9 (90%) performed for pain relief in polycystic kidney disease successfully produced immediate pain relief. Pain-free status decreased with time with 7 of 8 (87.5%) pain-free after 6 months, and 5 of 7 (71.4%) at 1, 4 of 6 (66.7%) at 2 and 1 of 4 (25%) at 3 years. A repeat operation successfully relieved recurrent pain in 2 of 3 cases (66.7%). Of the 7 patients with polycystic kidney disease who underwent surgery for pain relief 5 (71%) are currently pain-free. CONCLUSIONS: Laparoscopic renal cyst decortication is an effective minimally invasive treatment for painful simple cysts. It is also effective for short to intermediate pain relief in autosomal dominant polycystic kidney disease. Long-term followup suggests that a repeat procedure may be necessary to maintain adequate control of symptoms in polycystic kidney disease.     

Additive Manufacturing of 3D‐Architected Multifunctional Metal Oxides

Additive manufacturing (AM) of complex three‐dimensional (3D) metal oxides at the micro‐ and nanoscales has attracted considerable attention in recent years. State‐of‐the‐art techniques that use slurry‐based or organic–inorganic photoresins are often hampered by challenges in resin preparation and synthesis, and/or by the limited resolution of patterned features. A facile process for fabricating 3D‐architected metal oxides via the use of an aqueous metal‐ion‐containing photoresin is presented. The efficacy of this process, which is termed photopolymer complex synthesis, is demonstrated by creating nanoarchitected zinc oxide (ZnO) architectures with feature sizes of 250 nm, by first patterning a zinc‐ion‐containing aqueous photoresin using two‐photon lithography and subsequently calcining them at 500 ºC. Transmission electron microscopy (TEM) analysis reveals their microstructure to be nanocrystalline ZnO with grain sizes of 5.1 ± 1.6 nm. In situ compression experiments conducted in a scanning electron microscope show an emergent electromechanical response: a 200 nm mechanical compression of an architected ZnO structure results in a voltage drop of 0.52 mV. This photopolymer complex synthesis provides a pathway to easily create arbitrarily shaped 3D metal oxides that could enable previously impossible devices and smart materials.