The Relationships between HIV-1 Infection, History of Methamphetamine Use Disorder, and Soluble Biomarkers in Blood and Cerebrospinal Fluid

Round 1

Reviewer 1 Report

The manuscript entitled “The Relationships between HIV Infection, History of Methamphetamine Use Disorder, and Soluble Biomarkers in Blood and Cerebrospinal Fluid” by Walter et al. is an interesting paper describing and adding supporting new data to understand the combined effects of HIV-1 infection and methamphetamine (METH) use disorder on the immune system and cognitive function of people with HIV (PWH), and for identifying potential associated soluble biomarkers in the plasma and cerebrospinal fluid. To this aim, authors conducted a cross-sectional study collecting data from a total of 146 participants subdivided in four groups (control group, people with a history of a METH use disorder, PWH with no history of METH use disorder, and PWH with a history of METH use disorder), and found, after performing a  factor analysis, that the combination of HIV and METH use disorder was associated with higher levels of immune, vascular, and oxidative  stress biomarkers in the blood, as well as with worse memory.

The article is clear and well written, the results are well presented, the conclusions drawn are supported by the results obtained, and the findings give a potential improvement to the knowledge of the effects of HIV and methamphetamine use disorder on central immune function, thus it is suitable for publication in Viruses.

Author Response

We thank this reviewer for describing our paper as "interesting" and "clear and well-written" and for saying that it improves our knowledge of the field.

Since Reviewer 1 did not have any suggested edits, we are not providing a point-by-point response for this Reviewer.

Reviewer 2 Report

This study examined potential effects of HIV-1 status and methamphetamine use in relation to cognitive and affective status, as well as various biomarkers in plasma and CSF. Samples were collected from individuals that belong to four groups regarding HIV status and history of METH use (+/- for each), where the level of different biomarkers were measured (e.g. cytokines). The demographics differed somewhat between the four groups, for instance regarding age, sex and education, but were otherwise well-matched for HIV/METH characteristics. Factor analyses of plasma and CSF biomarkers revealed significant differences between the different groups for specific factors, which are composed of various immune, vascular or oxidative markers. Further analysis of cognitive and affective measures (multiple domains) were also investigated, which revealed only delayed recall as being significantly different between the H+/M+ vs. H-/M- groups. Correlation analysis of plasma factor 3 (a combination of 4 biomarkers) and delayed recall showed a negative correlation.

One seemingly minor but important point is to change all mentions of “HIV infection” HIV-1, unless a few are in fact HIV-2, and then to specify it as such. If that makes the paper more difficult to read, then one could at least specify it in the beginning and mention that each time one says HIV, they mean HIV-1.

The study is nicely done, well-controlled, scientifically and statistically sound. The conclusions do not overreach and based on the results; they are carefully worded. I don’t really have many corrections (except to say watch out for minor punctuation errors). My only concern is whether this study is best suited for being published in Viruses, esp. based on the significance of the results. Would it not be better suited for -say- Diagnostics, or another one of the many MDPI journals? It does not seem like the focus is on HIV-1 infection or the virus itself per se, rather potential physiological manifestations that come from synergistic effects of HIV-1 status and METH use. I personally do not quite see it as fitting within the scope of Viruses.

Author Response

We thank the reviewer for saying our study was, "nicely done, well-controlled, scientifically and statistically sound." A point-by-point response to comments follows below:

Comment 1: "One seemingly minor but important point is to change all mentions of “HIV infection” HIV-1, unless a few are in fact HIV-2, and then to specify it as such. If that makes the paper more difficult to read, then one could at least specify it in the beginning and mention that each time one says HIV, they mean HIV-1."

Response 1: We thank the reviewer for this clarifying suggestion. The HIV+ participants in this study were positive for HIV-1 only, not HIV-2. We have updated the manuscript to reflect this. We say HIV-1 at its first mention, noting that all subsequent mentions of "HIV" refer to "HIV-1."

Comment 2: "My only concern is whether this study is best suited for being published in Viruses, esp. based on the significance of the results. Would it not be better suited for -say- Diagnostics, or another one of the many MDPI journals? It does not seem like the focus is on HIV-1 infection or the virus itself per se, rather potential physiological manifestations that come from synergistic effects of HIV-1 status and METH use. I personally do not quite see it as fitting within the scope of Viruses."

Response 2: We submitted our manuscript to the Viruses Special Issue: HIV and Substances of Abuse. We think that our manuscript is perfectly suited for this Special Issue of Viruses because it examines methamphetamine use in people with HIV.