We determined the fidelity of avian myeloblastosis virus and Moloney murine leukemia virus reverse transcriptases (RTs) during DNA synthesis in vitro using the M13mp2 lacZ alpha gene as a mutational target. Both RTs commit an error approximately once for every 30,000 nucleotides polymerized. DNA sequence analysis of mutants generated in a forward mutation assay capable of detecting many types of errors demonstrated that avian myeloblastosis virus RT produced a variety of different mutations. The majority (58%) were single-base substitutions; all of which resulted from the misincorporation of either dAMP or dGMP. Minus-one frameshifts were also common, composing about 30% of the mutations. In addition to single-base events, eight mutants contained sequence changes involving from 2 to 59 bases. The frequency of these mutants suggests that, at least during DNA synthesis in vitro, RTs also commit errors by mechanisms other than classical base miscoding and misalignment. We examined the ability of RTs to synthesize DNA from a mismatched primer terminus at a sequence where the mismatched base was complementary to the next base in the template. Unlike cellular DNA polymerases which polymerize from the mismatched template-primer, RTs preferred to polymerize from a rearranged template-primer containing a matched terminal base pair and an unpaired base in the template strand. The unusual preference for this substrate suggests that the interactions between RTs and the template-primer are different from those of cellular DNA polymerases. The overall error rate of RT in vitro is sufficient to account for the estimated mutation rate of these viruses.

Avian Myeloblastosis Virus↗

PubMed1989

Hyponatremia in patients with the acquired immunodeficiency syndrome.

Of 103 patients with the acquired immunodeficiency syndrome (AIDS) admitted for acute opportunistic infections, 36 had serum sodium less than or equal to 130 mEq/l (130 mmol/l). In 12 the hyponatremia was associated with volume depletion and corrected with saline replacement therapy. In 23 it was associated with the syndrome of inappropriate antidiuretic hormones secretion (SIADH). One patient had adrenal insufficiency and the serum sodium corrected after steroid replacement. We conclude that hyponatremia is a common electrolyte abnormality in AIDS patients suffering acutely from opportunistic infections and that SIADH and volume depletion are important contributing factors.

Acquired Immunodeficiency Syndrome↗

PubMed1989

Evidence for an HIV-related nephropathy: a clinico-pathological study.

The existence of an HIV-related nephropathy as a distinct disease entity is controversial. We observed a high incidence of renal disease in our AIDS patients. Of 182 patients, 59 patients (32.4%) were found to have heavy proteinuria (greater than 2 g/24 h). Of these, 24 patients had slow progression of renal insufficiency and 2 patients had rapid deterioration to end stage renal disease. There was a notable absence of hypertension in these cases. The incidence of proteinuria was similar in blacks and hispanics; however 22.8% of blacks had renal insufficiency as compared to 6.9% of hispanics. There was no difference in the incidence of heavy proteinuria between intravenous drug abusers (32.3%) and nonabusers (33.3%). Renal morphology when examined showed characteristic changes, including cytomembranous structures and virus-like particles. These changes were similar in patients with heavy or light proteinuria, though they were less severe in the latter. We conclude that a HIV-related nephropathy exist and the presence of cytomembranous structures and virus-like particles in the renal tissue raises the possibility of a viral etiology for this disorder.

Acquired Immunodeficiency Syndrome↗

PubMed1989

Tubuloreticular inclusions in colonic mucosa as diagnostic markers of AIDS.

Tubuloreticular inclusions (TRI) are known to be associated with viral infections and are considered highly specific of the acquired immune deficiency syndrome (AIDS) in the appropriate clinical setting. We describe a homosexual man without any evidence of AIDS who presented with diarrhea. A search for the usual pathogens was unsuccessful, but electronmicroscopic examination of colonic mucosa revealed numerous tubuloreticular inclusions. The diarrhea subsided and 2 months later the patient developed Pneumocystis carinni pneumonia. This observation suggests that the detection of TRI in the colonic mucosa can precede the clinical manifestations of AIDS, and these structures can be useful markers for the future development of AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed1988

Lattice calculation of weak amplitudes of D and B mesons.

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Journal Article↗

PubMed1988

Mutagenesis by transient misalignment.

Based upon a consideration of two mutational hot spots produced during DNA synthesis by a eukaryotic DNA repair polymerase, we suggested that certain base substitution errors result not from direct miscoding but from correct coding by a transiently misaligned template-primer (Kunkel, T. A., and Alexander, P. S. (1986) J. Biol. Chem. 261, 160-166). This model, which we called dislocation mutagenesis, has been directly tested. Introducing a single, phenotypically silent G----A base change into the template switches the base substitution specificity at the immediately adjacent hot spot, a T residue, from T----G transversions to T----A transversions. The cumulative change in frequency, represented by the disappearance of the T----G events and the appearance of the T----A events, is greater than 300-fold. These data demonstrate that during DNA synthesis in vitro, a base at one position can code a mutation at another position. This mechanism can operate over greater distances to produce complex mutations as well. We present one example in which a 123-base deletion containing three base changes at one end of the deletion can be precisely explained by transient misalignment. It remains to be established whether mutagenesis by dislocation operates in vivo to produce biologically significant changes in genetic information.

Base Sequence↗